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THE UNIVERSITY OF CHICAGO COMPREHENSIVE CANCER CENTER
2010 – 2011
SCIENTIFIC R EPORT
FROM THE DIRECTOR
Dear Friends and Colleagues:
It gives me great pleasure to present The University of Chicago Comprehensive Cancer Center’s 2010 – 2011 Scientific Report. The report serves as an
account of the progress we have made during the past 2 years, an exciting
time marked by growth and development.
We have undertaken several initiatives to place personalized therapies at the
forefront of clinical care, including the development of the Center for Personalized Therapeutics. The center incorporates broad genetic information
into routine clinical practices to guide medical treatment decisions. We have
also received renewed funding for the Pharmacogenomics of Anticancer
Agents Research (PAAR) Group, which aims to improve the efficacy of cancer therapeutics. Another initiative is the
1000 Cancer Genome Project, which we launched to sequence the transcriptomes of 1000 tumors to identify new
therapeutic targets and facilitate personalized treatment strategies.
Adding to the repertoire of shared core facilities and further strengthening our population research efforts, we
developed the Epidemiology and Research Recruitment Core (ERRC) to streamline specimen collection and implement processes for large-scale collection of interview data to ascertain individual variables and exposure history. The
integration of these multiple dimensions allows investigators to conduct high-quality multidisciplinary population
and clinical research studies.
To serve our neighbors in the surrounding Chicago area better, in 2010 we established the Office of Community
Engagement and Cancer Disparities (OCECD). The OCECD facilitates University-community partnerships
through advocacy, education, and community-based research to decrease cancer health disparities, increase cancer
knowledge in the community, and increase participation in clinical trials. Thus far, the OCECD has made steady
progress in promoting breast cancer screening in Chicago’s black and Asian American communities.
Our growth is reflected in the 81 new cancer researchers who have joined the Cancer Center over the past 5 years.
These talented investigators have significantly enhanced our program with their high-quality expertise in the areas
of translational and clinical oncology, surgical oncology, pediatric oncology, and population research. With a total
cost of $93 million in peer-reviewed grant funding, our 220 researchers across six scientific programs have been
pioneering the research and development outlined throughout the pages of this report.
We continue to have the largest cancer clinical trials program in Illinois, with 900 patients enrolled into therapeutic
clinical trials in 2010. We also hold leadership positions in several national clinical trials study groups, and we are
one of only a handful of hospitals in the country that provides all three phases of clinical trials through programs
funded by the National Cancer Institute. Our New Hospital Pavilion, soon to be completed, will further facilitate
our distinguished clinical research efforts.
I am pleased to say that the past 2 years have been exhilarating as we have grown and undertaken opportunities
to explore new avenues in cancer research. I would like to thank our constituents for their generosity and support,
without which this work would not be possible. While we celebrate our accomplishments, we hold fast to our
mission to pursue the scientific efforts required to advance cancer care.
With gratitude,
Michelle M. Le Beau, PhD
Arthur and Marian Edelstein Professor of Medicine
Director, The University of Chicago Comprehensive Cancer Center
Leadership and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Overview of The University of Chicago
Comprehensive Cancer Center. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
Accomplishments of Note . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Molecular Mechanisms of Cancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Table of Contents
From the Director . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Inside Cover
Hematopoiesis and Hematological Malignancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
Immunology and Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
Advanced Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
Cancer Prevention and Control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
Clinical Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134
Resources and Services . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137
Highlights . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
UCCCC SCIENTIFIC REPORT 2010 – 2011
Pharmacogenomics and Experimental Therapeutics . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
1
UCCCC Leadership and Administration
UCCCC LEADERSHIP AND ADMINISTRATION
EXECUTIVE COMMITTEE
Michelle M. Le Beau, PhD
Director
Arthur and Marian Edelstein
Professor of Medicine
Director, Cancer
Cytogenetics Laboratory
Marcy A. List, PhD
Associate Director for
Administration
Scientific Director, Cancer
Clinical Trials Office
Marsha R. Rosner, PhD
Co-Deputy Director for
Basic Sciences
UCCC SCIENTIFIC REPORT 2010 – 2011 Charles B. Huggins Professor
Chair, Ben May Department for
Cancer Research
Professor of Neurobiology,
Pharmacology, and Physiology
Richard L. Schilsky, MD
Co-Deputy Director for
Clinical Sciences
Professor of Medicine and Section
Chief of Hematology/Oncology
Habibul Ahsan, MBBS, MMedSc
Associate Director for
Population Research
Professor of Health Studies,
Medicine, and Human Genetics
John Cunningham, MBBCh, MSc
Professor of Pediatrics and Section
Chief of Pediatric
Hematology/Oncology
Geoffrey L. Greene, PhD
Associate Director for Basic Sciences
Virginia and D.K. Ludwig Professor
Associate Director, Ben May
Department for Cancer Research
Yves Lussier, MD П†
Associate Director for Informatics
Associate Professor of Medicine
Director, Center for
Biomedical Informatics
2
Mark J. Ratain, MD
Associate Director for
Clinical Sciences
Walter Stadler, MD
Fred C. Buffett Professor of
Medicine and Surgery
Leon O. Jacobson Professor
of Medicine
Associate Dean for
Clinical Research
Director, Center for Personalized
Therapeutics
Director, Genitourinary Program
Director, Pharmacology
Core Facility
Gary Steinberg, MD
Bruce and Beth White Family
Professor of Surgery
Ravi Salgia, MD, PhD
Professor of Medicine
Michael Vannier, MD
Professor of Radiology
Associate Director for
Translational Sciences
Ezra Cohen, MD
Associate Professor of Medicine
Associate Director for Education
ADDITIONAL MEMBERS
OF THE CANCER
ADVISORY COMMITTEE
Susan Cohn, MD
Professor of Pediatric
Hematology/Oncology
Ralph Weichselbaum, MD
Daniel K. Ludwig Professor and
Chairman of Radiation &
Cellular Oncology
S. Diane Yamada, MD
Professor of Obstetrics
and Gynecology
Chief, Section of
Gynecological Oncology
Everett E. Vokes, MD
John E. Ultmann Professor and
Chairman of Medicine
Director, Pediatric Clinical Sciences
Karen E. Kim, MD, MS
Associate Professor of Medicine
Director, Office of Community
Engagement and
Cancer Disparities
Olufunmilayo Olopade, MBBS
Walter L. Palmer Distinguished
Service Professor of Medicine
Associate Dean for Global Medicine
Mitchell C. Posner, MD
Thomas D. Jones Professor and
Chief of General Surgery
James Schilling, PhD
Associate Director for
Core Facilities
Executive Director, Office of
Shared Research Facilities
Arieh Shalhav, MD
Fritz and Mary Lee Duda Chair,
Professor and Chief of Urology
PROGRAM LEADERS
MOLECULAR MECHANISMS OF CANCER
Suzanne Conzen, MD
Professor of Medicine
Kay MacLeod, PhD
Associate Professor, Ben May
Department for Cancer Research
HEMATOPOIESIS AND
HEMATOLOGICAL MALIGNANCIES
Wendy Stock, MD
Professor of Medicine
Director, Leukemia Program
Michael Thirman, MD
Associate Professor of Medicine
IMMUNOLOGY AND CANCER
Thomas Gajewski, MD, PhD
Professor of Pathology
and Medicine
φ  Dr. Lussier left UChicago in August 2011.
EXTERNAL ADVISORY
COMMITTEE
M. Eileen Dolan, PhD
Professor of Medicine
James Willson, MD (Chair)
Director, Harold Simmons
Cancer Center
Walter Stadler, MD
Fred C. Buffett Professor of
Medicine and Surgery
Associate Dean for Clinical Research
Director, Genitourinary Program
ADVANCED IMAGING
Lisa K. Simmons Distinguished
Chair and Professor in
Comprehensive Oncology
The University of Texas
Southwestern Medical Center
at Dallas
Gregory Karczmar, PhD
Professor of Radiology
Donald Berry, PhD
Professor and Chair of Biostatistics
Director, Magnetic Resonance
Imaging and Spectroscopy
Core Facility
M.D. Anderson Cancer Center
Heber MacMahon, MB, ChB
Professor of Radiology
Section Chief of
Thoracic Radiology
Habibul Ahsan, MBBS, MMedSc
Associate Director for
Population Research
Professor of Health Studies,
Medicine, and Human Genetics
Brian Chiu, PhD
Associate Professor of
Health Studies
Andrea King, PhD
Professor of Psychiatry
SENIOR STAFF
Natalie Olinger Boden
Director for Communications
and Public Relations
Mary Ellen Connellan, MA
Executive Director, The University
of Chicago Cancer Research
Foundation
Rajan Gopalakrishnan, MS
Director for Informatics
Hoyee Leong, PhD
Director for Scientific
Communications and
Strategic Partnerships
Christine Miller, MA
Director for Finance
Connie Skosey, RN, CCRP
Director for Clinical Operations
CEO, James Cancer Hospital &
Solove Research Institute
Professor of Cancer Research
Professor of Surgery
Duke University School
of Medicine
Gloria Petersen, PhD
Purvis and Roberta Tabor
Professor of Epidemiology
Mayo Clinic College of Medicine
Stephen E. Sallan, MD
Chief of Staff
Professor of Pediatrics
Harvard Medical School
Dana-Farber Cancer Institute
Lawrence Schwartz, MD
James Picker Professor and
Chairman of Radiology
Columbia University
The Ohio State University
Margaret R. Spitz, MD, MPH
Professor of Epidemiology
George T.Y. Chen, PhD
Professor of Radiation Oncology
Baylor College of Medicine
Massachusetts General Hospital
Daniel Sullivan, MD
Professor of Radiology
Mary B. Daly, MD, PhD
Timothy R. Talbot Jr. Chair for
Cancer Research
Professor and Chair of
Clinical Genetics
Fox Chase Cancer Center
Stan Gerson, MD
Director, Comprehensive
Cancer Center
Asa & Patricia Shiverick and Jane
Shiverick (Tripp) Professor of
Hematological Oncology
Case Western Reserve University
Steven D. Gore, MD
Professor of Oncology
The Sidney Kimmel Comprehensive
Cancer Center at Johns Hopkins
Duke University School of Medicine
Marcy Bohm Waldinger, MHSA
Chief Administrative Officer
University of Michigan
Comprehensive Cancer Center
Michael J. Weber, PhD
Director, Cancer Center
Professor of Microbiology
UCCCC SCIENTIFIC REPORT 2010 – 2011
CANCER PREVENTION
AND CONTROL
Michael A. Caligiuri, MD
Director, Comprehensive
Cancer Center
H. Kim Lyerly, MD
George Barth Geller Professor
in Cancer Research
UCCCC Leadership and Administration
PHARMACOGENOMICS AND
EXPERIMENTAL THERAPEUTICS
University of Virginia
Health System
Michael J. Welch, PhD
Professor of Radiology,
Developmental Biology,
Chemistry, and
Biomedical Engineering
Washington University School
of Medicine
Philip D. Greenberg, MD
Professor of Medicine
and Immunology
University of Washington
Scott J. Leischow, PhD
Professor of Medicine and
Public Health
The University of Arizona
3
UCCCC SCIENTIFIC REPORT 2010 – 2011 Molecular Mechanisms of Cancer
OVERVIEW
4
OUNDED IN 1973 UNDER THE LEADERSHIP OF JOHN E.
Ultmann, MD, The University of Chicago Comprehensive Cancer
Center (UCCCC) has a long tradition of transforming cancer care through innovative research in basic, translational, clinical, and population sciences. The UCCCC,
designated as a National Cancer Institute (NCI) Cancer Center in 1974 with the award
of the Cancer Center Support Grant (CCSG), has been recognized as a preeminent
leader in research to prevent cancer, elucidate its complexities, and develop novel
therapies for state-of-the-art patient care. Today, the UCCCC continues its reputation of excellence and innovation as one of only 40 NCI-designated comprehensive
cancer centers in the nation, and one of only two such centers in Illinois. Through the continuous support of the NCI centers in the nation, and one of
and the Biological Sciences Division over the only two such centers in Illinois.
past 37 years, the UCCCC has strengthened
and enhanced its mission to prevent, understand, and cure cancer. As a result of
scientific accomplishments, our members are awarded approximately $99 million in
research funding annually, with $33 million of this sum awarded by the NCI and over
$23 million in non-peer-reviewed grants and contracts. The current funding base for
the UCCCC, which includes 10 P01 and Center type grants, 9 U-series awards, and
2 SPORE/SCOR awards, represents a nearly 40% increase in total peer-reviewed
grant support since 2006. UCCCC SCIENTIFIC REPORT 2010 – 2011
The UCCCC’s scientific community integrates 220 members across 20 academic
departments and three University Divisions (Biological, Physical, and Social
Sciences). Our members specialize in fields across the continuum of cancer research
in a highly interactive environment. Research is organized around six established
scientific programs including Molecular Mechanisms of Cancer, Hematopoiesis
and Hematological Malignancies, Immunology and Cancer, Pharmacogenomics &
Experimental Therapeutics, Advanced Imaging,
and Cancer Prevention and Control. These Today, the UCCCC continues
programs emphasize translational and interdis- its reputation of excellence and
ciplinary research, and promote collaboration
innovation as one of only 40 NCIamong a diverse and dedicated team of outdesignated comprehensive cancer
standing researchers, physicians, and trainees. Overview
F
The UCCCC has been traditionally recognized for its strength in both basic and
clinical research, with a strong emphasis in the areas of cell signaling, cancer
genetics, and tumor immunology. For several decades, the UCCCC has been a
leader in the characterization of hematological malignant diseases, the development of new treatment paradigms in head and neck cancer, and in experimental
therapeutics and early phase clinical trials for cancer. In the last decade, we have
gained international recognition for our programs in personalized oncology, particularly pharmacogenetics of anticancer agents, and the identification of patients
at high risk for cancer, with an emphasis on minority populations. These successes
highlight the UCCCC’s commitment to bringing new diagnostic tests, novel treatments, and interventions to prevent cancer into medical practice.
5
Accomplishments of Note
Accomplishments of Note
Personalized Therapeutics
nThe UCCCC successfully renewed its NIH U01 Pharmacogenomics of Anticancer Agents Research
(PAAR) Group award, which aims to improve the efficacy of anticancer drugs by defining how
genetic variability impacts the variability in response to anticancer agents.
nThe University, under the leadership of Dr. Mark Ratain, developed the Center for Personalized
Therapeutics and is recruiting patients to a clinical study that incorporates broad genetic
information into routine clinical practice to guide medical treatment decisions.
nThe Laboratory for Molecular and Genomic Pathology (LMGP) is being developed to advance
molecular testing in cancer diagnosis and treatment. nThe UCCCC launched the Chicago 1000 Cancer Genome Project in conjunction with the Institute
for Genomics and Systems Biology (IGSB). Using the latest technologies in gene-sequencing
and computational analysis, the transcriptomes of 1000 tumors are being sequenced to identify
new therapeutic targets and facilitate personalized treatment strategies.
UCCCC SCIENTIFIC REPORT 2010 – 2011 Population Research
6
nThe UCCCC established the Epidemiology and Research Recruitment Core to support population
studies.
nThe Office of Community Engagement and Cancer Disparities (OCECD), directed by Dr. Karen
Kim, was established to facilitate University-community partnerships through advocacy,
education, and community-based research to decrease cancer health disparities, increase cancer
knowledge in the community, and increase participation in clinical trials.
n900 patients were entered onto therapeutic trials in 2010. These clinical efforts focus on studies
of new drugs, sequencing of multidisciplinary treatment, transplantation, organ preservation,
and treatment intensification as strategies to increase cure rates and response.
nThe Cancer Clinical Trials Office (CCTO) consolidated regulatory activities for all adult cancerrelated trials, developed “real-time”, web-based access for protocol priority trees, and developed
interfaces between databases for clinical trials management to streamline the retrieval and
transfer of clinical and patient demographic data.
Accomplishments of Note
Clinical Trials
nThe UCCCC and The University of Chicago Medical Center (UCMC) developed the Clinical Cancer
Programs Operations Group (CCPOG) to enhance clinical operations. Recruitment and Expansion
nOver the past 5 years, 81 new talented cancer researchers joined the UCCCC, including
faculty in translational and clinical oncology, pediatric oncology, surgical oncology, and
population research. nConstruction of the New Hospital Pavilion, opening in 2013, will provide 1.2 million square feet
of specialty care with a focus on cancer and advanced surgery.
UCCCC SCIENTIFIC REPORT 2010 – 2011
nThe UCMC developed a new partnership with Silver Cross Hospital (New Lenox, IL) to build a
20,000-square-foot outpatient cancer treatment center scheduled to open in early 2012.
7
MOLECULAR MECHANISMS OF CANCER
PROGRAM LEADERS
Kay Macleod, PhD
Associate Professor .
of the Ben May .
Department for .
Cancer Research
8
Suzanne D. Conzen, MD
Professor of Medicine
HE MOLECULAR MECHANISMS OF CANCER PROGRAM
comprises a diverse group of 46 investigators conducting basic
and translational research from 12 departments with specialties
including chemistry, systems biology, drug discovery, and developmental biology. The Program supports a collaborative environment
between basic scientists and clinical researchers who are dedicated
to elucidating the basic cell signaling and molecular mechanisms of
abnormal cell growth that could lead to the discovery of innovative
Molecular Mechanisms of Cancer
T
anticancer treatments. Particular emphasis is placed on understanding cell cycle regulation in cancerous versus normal cells, mechanistic
analysis of signal transduction and apoptotic pathways, determining
the structural biology of key proteins involved in cancer etiology,
T H E OV E R A L L G OA L S O F T H E P R O G R A M A R E TO :
UCCCC SCIENTIFIC REPORT 2010 – 2011
and delineating developmental pathways relevant to cancer. в– в– Elucidate the molecular mechanisms of tissue specific and
cell type-specific gene expression;
в– в– Determine the cellular mechanisms underlying cell growth/
division and cell survival/death;
в– в– Understand the multifaceted mechanisms leading to
cancer metastases;
в– в– Use large-scale, high-throughput, and systems biology
approaches to understand cancer biology; and
в– в– Discover novel developmental pathways relevant to
cancer cell signaling.
9
Molecular Mechanisms of Cancer
PROGRAM MEMBERSHIP†Eric Beyer, MD, PhD
Professor of Pediatrics
David Boone, PhD
Assistant Professor of Medicine
Steven Chmura, MD, PhD
Assistant Professor of Radiation
& Cellular Oncology
Suzanne Conzen, MD
Professor of Medicine
Wei Du, PhD
Professor of the Ben May
Department for Cancer Research
UCCCC SCIENTIFIC REPORT 2010 – 2011 Nickolai Dulin, PhD
Associate Professor of Medicine
Kathleen Goss, PhD
Assistant Professor of Surgery
Geoffrey Greene, PhD
Professor of the Ben May
Department for Cancer Research
Rex Haydon, MD, PhD
Associate Professor of Surgery
Tong-Chuan He, MD, PhD
Associate Professor of Surgery
Yu-Ying He, PhD
Assistant Professor of Medicine
Akira Imamoto, PhD
Associate Professor of the Ben May
Department for Cancer Research
Richard Jones, PhD
Assistant Professor of the Ben May
Department for Cancer Research
Shohei Koide, PhD
Associate Professor of Biochemistry
& Molecular Biology
Stephen Kron, MD, PhD
Professor of Molecular Genetics
& Cell Biology
Bruce Lahn, PhD
Professor of Human Genetics
Ernst Lengyel, MD, PhD
Professor of Obstetrics
& Gynecology
Marsha Rosner, PhD
Professor and Chair of the Ben May
Department for Cancer Research
Shutsung Liao, PhD
Professor of the Ben May
Department for Cancer Research
Benoit Roux, PhD
Professor of Biochemistry
& Molecular Biology
Anning Lin, PhD
Professor of the Ben May
Department for Cancer Research
Ravi Salgia, MD, PhD
Professor of Medicine
Hue Luu, MD
Assistant Professor of Surgery
Kay Macleod, PhD
Associate Professor of the Ben May
Department for Cancer Research
Elizabeth McNally, MD, PhD
Professor of Medicine
Ivan Moskowitz, MD, PhD
Assistant Professor of Pediatrics
Lucia Schuger, MD
Professor of Pathology
П†Stephen Skapek, MD
Associate Professor of Pediatrics
Julian Solway, MD
Professor of Medicine
Michael Spiotto, MD, PhD
Instructor of Radiation &
Cellular Oncology
Milan Mrksich, PhD
Professor of Chemistry
Jonathan Staley, PhD
Associate Professor of Molecular
Genetics & Cell Biology
Piers Nash, PhD
Assistant Professor of the Ben May
Department for Cancer Research
Wei-Jen Tang, PhD
Professor of the Ben May
Department for Cancer Research
Marcelo Nobrega, MD, PhD
Assistant Professor of
Human Genetics
Jerrold Turner, MD, PhD
Professor of Pathology
Clifton Ragsdale, PhD
Associate Professor of
Neurobiology
Ilaria Rebay, PhD
Associate Professor of the Ben May
Department for Cancer Research
Jalees Rehman, MD
Assistant Professor of Medicine
Carrie Rinker-Schaeffer, PhD
Professor of Surgery
Donald Vander Griend, PhD
Assistant Professor of Surgery
Samuel Volchenboum, MD,
PhD, MS
Assistant Professor of Pediatrics
Kevin White, PhD
Professor of Human Genetics
Yingming Zhao, PhD
Professor of the Ben May
Department for Cancer Research
Bernard Roizman, ScD
Professor of Molecular Genetics
& Cell Biology
Deborah Lang, PhD
Assistant Professor of Medicine
†  Reflects all Program membership during 2010-2011
φ  Individuals who are no longer at the UCCCC
10
Program Highlights††Due to space constraints, only a small representative sample of Program highlights is presented here.
TSC2 INACTIVATION
SPECIFICALLY KILLS RBMUTANT CANCER CELLS
PARP1 INHIBITOR
ACCELERATES SENESCENCE
IN IRRADIATED BREAST
CANCER CELLS AND TUMORS
(INTERPROGRAMMATIC)
The antitumor effects of ionizing
radiation (IR) are determined in
part by persistent DNA doublestrand breaks (DSB). IR induces
the modification of chromatin
domains surrounding DSBs, known
as IR-induced foci (IRIF), which are
implicated in DNA damage signaling and repair. An early event in the
DSB response is the recruitment and
activation of poly(ADP-ribose) polymerase 1 (PARP1). Stephen Kron,
MD, PhD, and Ralph Weichselbaum,
MD (Pharmacogenomics and Exper-
imental Therapeutics Program),
monitored the effects of PARP inhibition following IR of breast cancer
cells and tumors. DSB repair was
blocked by ABT-888 (veliparib), a
PARP inhibitor currently in clinical
trials, resulting in enhanced IRIF
persistence and accelerated tumor
cell senescence compared to IR alone.
These results support targeting DSBs
with PARP inhibitors as a potential
therapeutic strategy to enhance
radiation effectiveness. (Efimova et
al., Cancer Res 70:6277-82, 2010)
GEOMETRIC CUES INFLUENCE
DIFFERENTIATION OF
MESENCHYMAL STEM CELLS
(INTRAPROGRAMMATIC)
While significant efforts have been
made to understand the factors
that influence the differentiation of
mesenchymal stem cells (MSCs),
the forces governing lineage commitment remain poorly understood.
UCCCC SCIENTIFIC REPORT 2010 – 2011
Inactivation of the Retinoblastoma
(Rb) tumor suppressor is a common
event in most human cancers, but
very few approaches have targeted
this event for therapeutic effect.
Wei Du, PhD, recently performed
a genetic screen to identify genes
that modulate the cell death effects
of Rb inactivation in the developing eye of Drosophila. He observed
that inactivation of Tsc2 resulted in
synergistic killing of tumor cells that
are inactivated for pRb in both cell
culture and in xenograft models. The
synthetic lethality between loss of
Rb and loss of Tsc2 was explained by
the requirement for pRb to mitigate
against oxidative stress resulting from
increased protein synthesis and de
novo lipid synthesis in Tsc2 mutant
cells. These results suggest that
inactivation of Tsc2 in Rb-deficient
cancers could reduce tumor burden
and be therapeutically relevant. (Li
et al., Cancer Cell 17:469-80, 2010)
Molecular Mechanisms of Cancer
Publications
11
Molecular Mechanisms of Cancer
UCCCC SCIENTIFIC REPORT 2010 – 2011 12
MSCs may be involved in the stromal
support or etiology of several cancers.
Bruce Lahn, PhD, and Milan
Mrksich, PhD, demonstrated that
cell shape can influence the differentiation of MSCs to distinct lineages.
Cells exposed to a mixture of adipogenic and osteogenic differentiation
cues showed differential commitment depending on adhesive area,
subcellular curvature, and aspect
ratio. The results indicated that geometric features that increased myosin
contractility promoted osteogenesis,
whereas shapes of identical area that
disrupted contractility favored adipogenesis. These results indicate that
geometric shaping can influence the
factors that direct MSC fate that in
turn are relevant to understanding
the behavior of mesenchymal-like
tumor cells and metastasis. (Kilian et
al., PNAS 107:4872-7, 2010)
RAC3 IS A NEW PROONCOGENIC PARTNER OF
ERО± IN BREAST CANCER
Estrogen receptor alpha (ERО±)
plays an important role in breast
cancer development and response to
hormone-based therapies. Geoffrey
Greene, PhD, discovered a unique
role for RAC3, a Rho family
GTPase, as an ERО± coactivator. In
a combination of overexpression,
chemical inhibition, and siRNA
knockdown assays, RAC3 was
necessary for full ERО±-induced
expression of genes involved in
cell proliferation, migration, and
invasion. Furthermore, RAC3 overexpression in ERО±-positive breast
cancers correlated with a significant
decrease in recurrence-free survival
and an increase in the odds ratio
for metastastic events. These results
indicate a novel function for Rhofamily GTPases and a potential new
therapeutic target for breast cancers
expressing ERО±. (Walker et al.,
Oncogene 30:1984-94, 2011)
GENETIC ANALYSIS OF WHOLEGENOME DATA REVEALS
DRIVING MUTATIONS OF A
HEPATOCELLULAR CARCINOMA
A central issue in cancer genomics
is understanding the dynamics of
tumor growth in relation to underlying somatic mutations. Cancer
mutations are classified as driver
mutations when they contribute
directly to tumorigenesis and are
critical for understanding the
molecular biology of cancers. Using
a cell-population genetic approach,
Chung-I Wu, PhD, in collaboration
with Kevin White, PhD, analyzed
a case of hepatocellular carcinoma
(HCC) to identify candidate driver
mutations. Nine different sections
from three tumors and seven
additional sections from adjacent
non-tumor tissues were sampled and
subjected to exon and whole-genome
sequencing.
Four
evolutionary
lineages of tumor cells were defined
from validated somatic mutations.
These lineages were derived from
three driver mutations affecting cell
cycle control and apoptosis, which
were functionally distinct from
mutations that accumulated earlier.
The distinct functions between these
mutations suggest that genetic interactions underlie tumor growth. (Tao
et al., PNAS 108:12042-7, 2011)
C-MET AND VEGFR-2 ACTIVITY
ARE REQUIRED FOR OVARIAN
CANCER METASTASIS
(INTERPROGRAMMATIC)
Targeted therapies have not yet
been approved for the treatment of
ovarian cancer. Ernst Lengyel, MD,
PhD, S. Diane Yamada, MD (Pharmacogenomics and Experimental
Therapeutics Program), and colleagues investigated the efficacy and
mechanism of action of foretinib, an
orally available multikinase inhibitor
of c-Met and vascular endothelial
growth factor receptor-2 (VEGFR2) against ovarian cancer growth.
Foretinib blocked tumorigenesis and
reduced invasive tumor growth in
genetic and xenograft mouse models
by inhibiting c-Met activation,
inducing cell cycle arrest, reducing
ovarian cancer cell adhesion and
migration, and inducing anoikis.
This study provides a rationale for
further clinical development of
foretinib as a targeted therapeutic for
ovarian cancer. (Zillhardt et al., Clin
Cancer Res 17:4042-51, 2011)
Grants
UVA-INDUCED SKIN CANCER
INVOLVES PTEN SUPPRESSION
Ultraviolet (UV) radiation is the
major environmental risk factor for
non-melanoma skin cancer. Yu-Ying
He, PhD, the recipient of an R01
award from the National Institutes
of Health, has demonstrated that
PTEN is a critical suppressor for
human and mouse skin cancer and
aims to determine the molecular
consequences of UVA-induced
PTEN down-regulation. This work
will provide new insights into the
molecular basis for UVA contribution in skin carcinogenesis.
CHRONIC STRESS IMPACTS
BREAST CANCER OUTCOME
Mechanisms that underlie the role
of chronic stress in breast cancer are
poorly understood. Suzanne Conzen,
MD, and Martha McClintock, PhD
(Cancer Prevention and Control
Program) were awarded an R01 grant
from the National Cancer Institute
to uncover novel stress-induced
mechanisms affecting mammary
tumor growth using rodent models
of breast cancer previously developed to study the impact of chronic
social isolation. Completion of these
studies will help identify preventive
interventions aimed at the identified
biological processes for women who
are at high risk of social isolation.
TRNA IS A POTENTIAL BREAST
CANCER THERAPEUTIC AGENT
Funded by the Department of
Defense Breast Cancer Program,
Marsha Rosner, PhD, is developing
ORGANOTYPIC
3-DIMENSIONAL CULTURE
IS ADAPTED FOR HIGHTHROUGHPUT SCREENING
Current drug screening strategies rely
on cell lines cultured on plastic, which
are poorly representative of the tumor
microenvironment. Ernst Lengyel,
MD, PhD, developed an organotypic
3D culture derived from primary
human mesothelial cells, fibroblasts,
and extracellular matrix. When
co-cultured with primary ovarian
cancer cells, the 3D culture mimics
early events that occur in adhesion,
invasion, and metastasis. Dr. Lengyel
was awarded an R21 grant from
the National Institutes of Health to
establish a robust and reproducible
high-throughput drug screening
assay using this 3D culture system.
Successful adaptation of the system
will facilitate the identification of new
therapeutic compounds and serve as
a proof-of-concept for using organotypic cultures for other drug screens.
ADVANCED MULTI-COLOR
CONFOCAL AND FRAP-SAC
MICROSCOPE ENHANCES
IMAGING CAPABILITIES
Jerrold Turner, MD, PhD, received
an S10 shared instrument grant from
the National Center for Research
Resources to acquire the Marianas
Real Time Confocal SDC microscopy system for incorporation into
the Integrated Microscopy Core
Facility, which serves over 165 laboratories at The University of Chicago
and multiple collaborative users from
neighboring institutions. The highspeed system provides users with new
features including SAC, FRET, and
FRAP, has simultaneous two-color
imaging capabilities, and serves as
an additional multicolor confocal
platform for live samples.
Molecular Mechanisms of Cancer
a new class of RNA-based agents to
treat breast tumors. Dr. Rosner has
engineered specific transfer RNAs
(tRNAs) that are mischarged, or
have incompatibly charged amino
acid and decoding capacity, which
leads to the synthesis of mutated
proteins that can fold incorrectly
and induce apoptosis. This potential
new therapeutic approach targets an
essential part of the cellular machinery, making it extremely difficult for
tumor cells to evolve and develop
resistance to this approach.
UCCCC SCIENTIFIC REPORT 2010 – 2011
13
Featured Faculty Profiles†UCCCC SCIENTIFIC REPORT 2010 – 2011 Molecular Mechanisms of Cancer
†Due to space constraints, only a small representative sample of Program members is presented here.
GEOFFREY GREENE, PHD
Professor of the Ben May Department for Cancer Research
Dr. Geoffrey Greene’s laboratory studies the molecular mechanisms by which
steroids and SERMs regulate development, differentiation, cellular proliferation and survival in hormone-responsive tissues and cancers, via one or both of
the two estrogen receptor subtypes, ERО± and ERОІ. Projects in his laboratory
have direct relevance and application to breast cancer genesis, progression,
treatment and prevention, as well as to the development of compounds that
can be used for hormone replacement therapy in postmenopausal women.
The overall objective of Dr. Greene’s research is to determine the molecular
distinctions between estrogen agonism and antagonism in hormone-dependent tissues and cancers, and to use this information to identify, develop,
and characterize novel compounds that can be used for hormone replacement
therapy and as breast cancer chemoprevention and chemotherapeutic agents.
Natural and synthetic ligands regulate diverse signaling and transcriptional
networks via one or both of two estrogen receptor subtypes, ERО± and ERОІ.
Geoffrey Greene, PhD
The structural and functional events underlying ligand-specific coregulator
recruitment and resultant transcriptional activation or repression are complex
and still not well defined for both ERs. However, the development of diverse ER subtype-selective
ligands has provided powerful molecular tools to study the linkage between ligand and transcription. Detailed structure-function information for the two ERs, a major focus of Dr. Greene’s
laboratory, has proved useful both for understanding as well as designing ligands with tissue- and
pathway-selective behaviors. Structural information for ERО± and ERОІ ligand-binding domains
(LBDs) occupied by some of these ligands has helped define the relationship between receptor
ligand positioning and the formation of different cofactor-binding surfaces. Combined with
knowledge gained from extensive genomic and proteomic mapping studies of ER target genes and
interacting proteins for both ER subtypes, it should be possible to improve breast cancer treatment
and prevention strategies.
In recent work, Dr. Greene’s laboratory identified RAC3 as a novel ERα co-regulator. RAC3 is
a Rho family small GTPase that is associated with cytoskeletal rearrangement.1 Notably, RAC3
appears to be necessary for full ERО± transcriptional activity and promotes proliferation and
migration in ERО±-positive breast cancer cells. In addition, RAC3 overexpression in ERО±-positive
breast cancers correlates with a significant decrease in recurrence-free survival and a significant
increase in the odds ratio of metastasis. Dr. Greene is exploring RAC3 as a potential therapeutic
target in ERО±-positive breast cancers that become therapy resistant.
1 Walker MP, Zhang M, Le TP, Wu P, LainГ© M, Greene GL. RAC3 is a pro-migratory co-activator of ERО±. Oncogene 30:19841994, 2011.
14
Professor of the Ben May Department for Cancer Research
Dr. Yingming Zhao’s research aims to develop new proteomics and chemical
biology approaches for studying protein post-translational modification
(PTM) pathways. He applies these technologies, in conjunction with those in
biochemistry and molecular and cell biology, to discover and characterize new
PTM pathways that have important implications in cancer.
Dr. Zhao’s laboratory has recently described the identification and verification of a previously
unreported form of PTM, lysine succinylation.1 The succinyllysine residue was initially identified by mass spectrometry and then exhaustively verified by various chemical and biochemical
methods. They further showed that lysine succinylation is evolutionarily conserved, and that this
PTM dynamically responds to different physiological conditions and exhibits different profiles
among cancer cell lines. The high abundance of succinyllysine and the roles of other known lysine
modifications in cancer biology suggest that lysine succinylation may also play a role in cancer.
Dysregulation of histone modifications is intimately associated with cancer progression. Dr.
Zhao’s group has identified 67 novel histone marks, a discovery that increases the current number
of known histone marks by about 70%.2 They verified one of the newly identified marks, lysine
crotonylation (Kcr), as a novel, evolutionarily conserved histone PTM. The unique structure and
genomic localization of histone Kcr suggest that it is mechanistically and functionally different
from histone lysine acetylation. These results dramatically extend the repertoire of histone PTM
sites and reveal new insights into epigenetic regulations.
UCCCC SCIENTIFIC REPORT 2010 – 2011
A major focus of the Zhao group is quantitative proteomics and the functional analysis of SIRT1, a protein that plays an important role in cancer and
aging. To characterize networks regulated by SIRT1, Dr. Zhao’s laboratory
identified and quantified 4623 Lys acetylation sites in 1800 Lys acetylation
proteins, representing the largest Lys acetylome reported to date. A total of
486 Lys acetylation sites were enhanced more than 100% in response to
SIRT1 knockout, notably among proteins involved in DNA damage response,
cell cycle, Notch signaling, and RNA splicing pathways. The results indicate
that SIRT1 targets mainly nonhistone proteins, but may indirectly regulate
Yingming Zhao, PhD
the acetylation levels of many additional substrates, including histones,
through modulation of acetylase activity. These efforts provide key insights
into mechanisms of SIRT1 functions and offer biomarker candidates for clinical evaluation of
SIRT1-activator compounds.
Molecular Mechanisms of Cancer
YINGMING ZHAO, PHD
1 Zhang Z, Tan M, Xie Z, Dai L, Chen Y, Zhao Y. Identification of lysine succinylation as a new post-translational modification. Nat
Chem Biol 7:58-63, 2011.
2 Tan M, Luo H, Lee S, Jin F, Yang JS, Montellier E, Buchou T, Cheng Z, Rousseaux S, Rajagopal N, Lu Z, Ye Z, Zhu Q, Wysocka
J, Ye Y, Khochbin S, Ren B, Zhao Y. Identification of 67 histone marks and histone lysine crotonylation as a new type of histone
modification. Cell 146:1016-1028, 2011.
15
Molecular Mechanisms of Cancer
WEI DU, PHD
Professor of the Ben May Department for Cancer Research
Dr. Wei Du’s laboratory uses an in vivo approach to investigate the coordination of cell proliferation with differentiation during normal animal
development, as well as how cells and tissues behave in response to specific
genetic alterations that are frequently observed in cancer. Many of the
genes that participate in these aspects of biology are well-conserved between
mammals and the fruit fly Drosophila melanogaster. The fly model is an
experimentally tractable and relatively simple genetic model system. Work
in the Du laboratory aims to understand how genes from distinct signaling
pathways work together to achieve proper tissue development and homeostasis, and to integrate discoveries from the fly with the more complex mouse and
human model systems. This approach has yielded several novel findings over
the past decade that have contributed to our understanding of developmental
processes and tumor biology.
UCCCC SCIENTIFIC REPORT 2010 – 2011 Wei Du, PhD
The Retinoblastoma (Rb) tumor suppressor is frequently inactivated in a variety
of cancers, so understanding how Rb-deficient cells rely on the activities of
distinct genes to grow and survive could lead to novel therapeutic targeting
that specifically kills tumor cells but not normal tissue. One such target identified by a genetic
screen in the Du laboratory is Tsc2, which was found to be important for cell survival in the
absence of Rb in both flies and human cells cultured under stress conditions.1 Inactivation of
Tsc2 specifically kills Rb-deficient cells, a phenotype that depends on elevated levels of oxidative
stress, and prevents tumor formation when xenografted into mice. Ongoing work on this project
aims to understand the sensitivity of these cells to various other forms of stress, and seeks to
identify methods to enhance or mimic this “synthetic lethal” effect of targeting Tsc2 activity in
cells lacking Rb.
Another major goal of the Du laboratory is to utilize the developing fly retina as a model to understand how cells coordinate a differentiation program with cell cycle arrest. Recent work on this
project showed that expression of Atonal is dynamically controlled by a network of eye-specific
genes, called the retinal determination factors, in collaboration with genes involved in diverse
developmental programs. Previous results showed that the transition from a proliferative progenitor state to a quiescent differentiated state during retinal development involves Atonal activity,
which controls expression of the CIP/KIP ortholog and cell cycle inhibitor Dacapo. Further
studies into how specific developmental genes function together with the retinal determination
factors during eye development are currently under way.
1 Li B, Gordon GM, Du CH, Xu J, Du W. Specific killing of Rb mutant cancer cells by inactivating TSC2. Cancer Cell
17:469-480, 2010.
16
Professor of Obstetrics/Gynecology
Dr. Ernst Lengyel’s clinical practice focuses on the surgical treatment of
primary and recurrent ovarian cancer. His research aims to understand
ovarian cancer tumor biology and translate findings into novel therapeutic
treatments that will significantly improve the survival of those with this
devastating disease. Ovarian cancer is the 5th leading cause of cancer deaths
among women in the United States and has the highest mortality rate of all
gynecologic malignancies. Following malignant transformation of ovarian
surface epithelial cells, tumor cells detach from the ovary and attach to the
peritoneum or omentum, but rarely leave the peritoneal cavity.1 The disease
is often diagnosed at a late stage when tumor cells have disseminated within
the peritoneal cavity. Despite aggressive treatment, more than two thirds of
all patients succumb to their disease within 5 years.
Dr. Lengyel’s group uses primary and cultured ovarian cancer cell lines and mouse models of
ovarian cancer (xenograft, genetic). They have also assembled 12 tissue microarrays using primary
and metastatic ovarian tumor samples obtained from 200 patients. These samples are linked to a
database containing prospective clinicopathologic and survival data on all patients with ovarian
cancer that have undergone operations at The University of Chicago since 1992.
His laboratory collaborates with gynecologic pathologists from the Department of Pathology as well as researchers from the Department of Biochemistry and Molecular Biology.
Recent work has demonstrated that the receptor tyrosine kinase c-Met may be a good
therapeutic target for breast and ovarian cancers, and that integrins can activate c-Met in
a ligand-independent manner.2-4 Similarly, he has shown that targeting the urokinase plasminogen activator receptor (u-PAR) pathway in ovarian cancers is effective in preclinical
studies.5 Dr. Lengyel is also exploring new MRI contrast agents to differentiate benign from
malignant ovarian tumors in collaboration with Northwestern University’s Division of
Hematology/Oncology.
1
UCCCC SCIENTIFIC REPORT 2010 – 2011
Projects in Dr. Lengyel’s laboratory aim to: 1) understand the early steps of
ovarian cancer metastasis to the peritoneum and omentum and characterize
Ernst Lengyel, MD, PhD
tumor-stroma interactions during metastasis; 2) characterize and test new
treatment targets in pre-clinical models; 3) investigate new agents to delay
or inhibit the development of ovarian cancer; and 4) study the role of miRNAs in ovarian
cancer metastasis.
Molecular Mechanisms of Cancer
ERNST LENGYEL, MD, PHD
Lengyel E. Ovarian cancer development and metastasis. Am J Pathol 177:1053-1064, 2010.
2 Zillhardt M, Park SM, Romero I, Sawada K, Montag AG, Krausz T, Yamada SD, Peter ME, Lengyel E. Foretinib (GSK1363089)
an orally available multi-kinase inhibitor of c-Met and VEGFR-2, blocks proliferation, induces anoikis, and impairs ovarian cancer
metastasis. Clin Cancer Res 17:4042-4051, 2011.
Zillhardt M, Christensen J, Lengyel E. An orally available small molecule inhibitor of c-Met, PF-2341066, reduces tumor burden
in a pre-clinical model of ovarian cancer metastasis. Neoplasia 12:1-10, 2010.
3
Mitra AK, Sawada K, Tiwari P, Mui K, Gwin K, Lengyel E. Ligand independent activation of c-Met by fibronectin a5b1-integrin
regulates ovarian cancer invasion and metastasis. Oncogene 30:1566-1576, 2011.
4
5 Kenny HA, Leonhardt P, Ladanyi A, Yamada SD, Montag AG, Im HK, Jagadeeswaran S, Shaw DE, Mazar AP, Lengyel E.
Targeting the urokinase plasminogen activator receptor inhibits ovarian cancer metastasis. Clin Cancer Res 17:459-471, 2011.
17
Molecular Mechanisms of Cancer
UCCCC SCIENTIFIC REPORT 2010 – 2011 RAVI SALGIA, MD, PHD
Professor of Medicine
Dr. Ravi Salgia, a physician-scientist with particular expertise in lung cancer, is
the director of the Thoracic Oncology Program at The University of Chicago.
He has been a clinical thoracic oncologist for nearly two decades and led
research efforts to study key pathways in lung cancer and the potential for novel
therapeutics. Early in his career, Dr. Salgia was the first to identify the inhibition of c-Kit with imatinib in vitro as well as the modulation of topoisomerase-I
by c-Kit modulation. He has developed and participated in numerous clinical
protocols, and has been instrumental in bringing together investigators from
diverse fields to collaborate on lung cancer studies.
Dr. Salgia’s laboratory was the first to identify the role of c-Met in lung
cancer. Specifically, his laboratory identified particular mutations in the juxtamembrane and semaphorin domains of c-Met. His group also showed the
regulation of the cytoskeleton with the juxtamembrane mutations of c-Met,
especially as related to the focal adhesion protein paxillin. Furthermore,
Ravi Salgia, MD, PhD
Dr. Salgia has determined the biological functions of the c-Met/hepatocyte
growth factor, as well as the potential for novel therapeutic inhibition.
Through this work, a number of clinical trials have come to fruition. Aside from his expertise in
tyrosine kinases, cytoskeletal regulation, topoisomerase-I, and downstream signal transduction
molecules, Dr. Salgia and his group have initiated studies to determine the role of EPH receptors
and reactive oxygen species in lung cancer.
Dr. Salgia and colleagues have developed a comprehensive thoracic oncology database that
combines clinical data with genomic and proteomic data obtained from various tumor tissues
collected from patients with non-small cell lung cancer.1 This database will aid in the identification of potential therapeutic targets for thoracic malignancies. In recent studies, Dr. Salgia and
his collaborators have demonstrated the potential for MST1R, a member of the MET receptor
tyrosine kinase family, as a therapeutic target in gastroesophageal cancer, and also PKC-ОІ and
VEGFR2 as therapeutic targets in malignant pleural mesothelioma.2,3
1 Surati M, Robinson M, Nandi S, Faoro L, Demchuk C, Rolle CE, Kanteti R, Ferguson BD, Hasina R, Gangadhar TC, Salama AK,
Arif Q, Kirchner C, Mendonca E, Campbell N, Limvorasak S, Villaflor V, Hensing TA, Krausz T, Vokes EE, Husain AN, Ferguson
MK, Karrison TG, Salgia R. Proteomic characterization of non-small cell lung cancer in a comprehensive translational thoracic
oncology database. J Clin Bioinforma 1:1-11, 2011.
2 Catenacci DV, Cervantes G, Yala S, Nelson EA, El-Hashani E, Kanteti R, El Dinali M, Hasina R, Brägelmann J, Seiwert T,
Sanicola M, Henderson L, Grushko TA, Olopade O, Karrison T, Bang YJ, Kim WH, Tretiakova M, Vokes E, Frank DA, Kindler HL,
Huet H, Salgia R. RON (MST1R) is a novel prognostic marker and therapeutic target for gastroesophageal adenocarcinoma. Cancer
Biol Ther 12:9-46, 2011.
3 Loganathan S, Kanteti R, Siddiqui SS, El-Hashani E, Tretiakova M, Vigneswaran H, Cervantes G, Natarajan V, Husain AN,
Vokes EE, Kindler HL, Salgia R. Role of protein kinase C ОІ and vascular endothelial growth factor receptor in malignant pleural
mesothelioma: Therapeutic implications and the usefulness of Caenorhabditis elegans model organism. J Carcinog 10:4, 2011.
18
Assistant Professor of the Ben May Department for Cancer Research
Dr. Richard Jones’ laboratory is focused on understanding the role of receptor
tyrosine kinase signaling networks in breast cancer. His group is developing
and applying large scale protein analysis methods for monitoring the abundance, modification, and localization of signaling proteins and transcription
factors involved in breast cancer progression.
The specific aims of his research are to: 1) characterize the phosphorylationdependent protein interactions between ErbB receptors and their downstream
mediators; 2) characterize the dynamic changes in protein abundance and
modification that occur in tumor cells stimulated by members of the ErbB
family; and 3) use computation modeling methods to describe the relationships between proteins in signaling networks and between proteins and cell
behaviors, especially migration and invasion.
Ciaccio MF, Wagner JP, Chuu C-P, Lauffenburger DA, Jones RB. Systems analysis of EGF receptor signaling dynamics with
microwestern arrays. Nat Methods 7:148–155, 2010.
1
2 Liu J, Kuo WL, Seiwert TY, Lingen M, Ciaccio MF, Jones RB, Rosner MR, Cohen EEW. Effect of complementary pathway blockade
on efficacy of combination enzastaurin and rapamycin. Head Neck 33:1774-1782, 2011.
3 Chevrier N, Mertins P, Artyomov MN, Shalek AK, Garber M, Iannacone M, Ciaccio MF, Gat-Viks I, Eisenhaure TM, Clauser
KR, Yosef N, Tonti E, Robinson J, Sutton A, Andersen MS, Root DE, von Andrian U, Jones RB, Park H, Carr SA, Regev A, Amit I,
Hacohen H. Systematic discovery of TLR signaling components delineates viral-sensing circuits. Cell 147:853-867, 2011.
UCCCC SCIENTIFIC REPORT 2010 – 2011
In the past year, the Jones laboratory has described the application of the
Richard Jones, PhD
micro-western array methodology in building statistical models of ErbB
1
receptor tyrosine kinase coactivation networks in cervical carcinoma cells.
They have additionally used this methodology to assist others in understanding the role of targeting multiple signaling pathways in head and neck cancer, and in understanding conflicting cell
signals in dendritic cells.2,3 Dr. Jones has also recently described the use of novel protein analysis
methodologies for understanding complex biological systems.4
Molecular Mechanisms of Cancer
RICHARD JONES, PHD
4 Hause RJ, Kim HD, Leung K, Jones RB. Targeted protein-omic methods are bridging the gap between proteomics and hypothesisdriven protein analysis approaches. Expert Rev Proteomics 8:565-575, 2011.
19
Molecular Mechanisms of Cancer
KAY MACLEOD, PHD
Associate Professor of the Ben May Department for Cancer Research
Work in Dr. Kay Macleod’s laboratory explores the role of autophagy and
mitochondrial function in cancer.1 Her work centers on two main avenues
of investigation: 1) the role of BNip3 and other regulators of mitochondrial
function and integrity in tumor cell metabolism and progression to metastasis, and 2) the role of autophagy in regulating tumor cell migration and
invasion, and how autophagy influences metastasis in vivo.
UCCCC SCIENTIFIC REPORT 2010 – 2011 Kay Macleod, PhD
The goals of Dr. Macleod’s research are focused on understanding how these
processes modulate breast cancer progression to metastasis through the use
of mouse models of breast cancer and primary human breast cancer cells
in collaboration with clinical oncologists. Using these in vivo approaches
and leveraging molecular, biochemical, and cell biological techniques, Dr.
Macleod’s research aims to understand how tumors subvert normal responses
to nutrient deprivation to promote cell migration/invasion and to activate
oxidative stress responses that promote tumor growth and metastasis.
For example, the Macleod laboratory has shown that BNip3 promotes
mitochondrial integrity, reduces oxidative stress and suppresses mammary tumor metastasis by
inhibiting Hif-1a stabilization and reducing tumor angiogenesis.2 Furthermore, BNip3 inhibits
tumor cell proliferation by regulating mitochondrial fragmentation in a cell cycle-dependent
manner.3 They have also shown that autophagy promotes tumor cell migration/invasion in vitro
and cancer metastasis in vivo through effects on focal adhesion activity.4 By understanding how
these processes contribute to cancer metastasis, the goal will be to determine how inhibiting
autophagy or aspects of mitochondrial function can prevent breast cancer metastasis. Along these
lines, Dr. Macleod has shown that autophagy-inducing drugs synergize with agents that cause
endoplasmic reticulum stress, resulting in enhanced tumor cell killing in vitro and in vivo.5
1
Glick D, Barth S, Macleod KF. Autophagy: Cellular & Molecular Mechanisms. J Pathol 221:3-12, 2010.
2 Tracy K, Chen H, Gwinn K, Zhang Y, Rehmann J, Dorn GW II, Macleod KF. Suppression of metastasis by BNIP3 through effects
on mitochondrial function and ROS. Genes Dev (under review).
3 Barth S, Zhou Y, Yang J, Zhao Y, Macleod KF. Cdk regulation of BNIP3 modulates mitochondrial ROS production during cell
cycle. Mol Cell Biol (under review).
4 Sharifi M, Olson L, Chen H, Collier C, Mui S, Macleod KF. Autophagy promotes cell motility and tumor metastasis through effects
on focal adhesion maturation. Cancer Res (in preparation).
5 De Raedt T, Walton Z, Lucas J, Li D, Chen Y, Maertens O, Jeong SM, Bronson RT, Normant E, Haigis MC, Manning BD, Wong
K-K, Macleod KF, Cichowski, K. Developing an mTOR-inhibitor based combination cancer therapy. Cancer Cell, 2011 (in press).
20
Assistant Professor of Pediatrics
Dr. Volchenboum’s laboratory is focused on using quantitative proteomics to
study pediatric solid tumors. Neuroblastoma is the most common pediatric
solid tumor and is responsible for 15% of deaths in children from cancer.
Despite aggressive multimodal therapy, most children with high-stage
neuroblastoma will die from their disease. The most powerful non-clinical
prognostic indicator of aggressive disease is amplification of the MYCN
oncogene. Using SILAC labeling and mass spectrometry-based proteomics,
Dr. Volchenboum is probing for differences between neuroblastoma cell lines
that over-express the MYCN oncogene and those that do not. Differentially
expressed proteins are confirmed by antibody-based methods.
The initial findings from this algorithm development were recently published (Mol Cell Proteomics 8:2011, 2009). In this study, Dr. Volchenboum’s laboratory demonstrated that spectral
deconvolution through comparison of stable isotope-labeled and unlabeled peptides facilitated
the classification of fragmentation ions as shifting or non-shifting. Next, they demonstrated that
they could compare these groups of ions to the theoretical fragmentation pattern of the Mascot
search engine-identified peptide to corroborate peptide identification. The algorithm significantly
improved the sensitivity and specificity of the mass spectrometry analysis when compared to the
Mascot search engine. A follow-up study using these methods on data from breast cancer cell
lines is now being prepared for submission, and another manuscript describing the algorithm for
identification of peptides directly from fragmentation spectra is in the final stages of development.
UCCCC SCIENTIFIC REPORT 2010 – 2011
Dr. Volchenboum’s laboratory is incorporating biological pathway analysis to
integrate proteomic and genomic expression data to understand the signaling
pathways perturbed as a result of MYCN amplification and over-expression.
Identification of important signaling pathways may lead to the development
Samuel Volchenboum, .
MD, PhD, MS
of new targeted therapeutics. Another major scientific interest is the development of algorithms to facilitate high-throughput proteomic analysis. The
current state-of-the-art methods for analysis of mass spectrometry data are highly inefficient,
owing to off-line analysis that prevents modulation of data collection during the run with consequent low sensitivity and narrow dynamic range. Furthermore, current methods for protein
identification rely on statistical analysis and are prone to a high false positive rate. Using stable
isotope-labeled proteomic data, Dr. Volchenboum is developing methods for rapid confirmation of
peptide identity based on spectral deconvolution and comparison to the fragmentation pattern of
the search engine-identified peptide. They are currently extending these methods to permit rapid
peptide identification directly from the captured spectra. By increasing the sensitivity and specificity of mass spectrometry-based proteomics, analysis of patient samples such as tumor biopsies or
serum may be performed in real-time, rapidly enough for clinically relevant decision-making.
Molecular Mechanisms of Cancer
SAMUEL VOLCHENBOUM, MD, PHD, MS
21
Selected Publications
Molecular Mechanisms of Cancer
* : Intraprogrammatic Collaboration
# : Interprogrammatic Collaboration
BEYER, ERIC, MD, PHD
Allen MJ, Gemel J, Beyer EC, Lal R.
Atomic force microscopy of Connexin40
gap junction hemichannels reveals
calcium-dependent
three-dimensional
molecular topography and open-closed
conformations of both the extracellular and cytoplasmic faces. J Biol Chem
286:22139-46, 2011. PMC3121358
Lichtenstein A, Minogue PJ, Beyer EC,
Berthoud VM. Autophagy: a pathway that
contributes to connexin degradation. J
Cell Sci 124:910-20, 2011. PMC3048889
UCCCC SCIENTIFIC REPORT 2010 – 2011 BOONE, DAVID, PHD
Mitra S, Sammani S, Wang T, Boone
DL, Meyer NJ, Dudek SM, MorenoVinasco L, Garcia JG, Jacobson JR. Role
of GADD45a in Akt Phosphorylation
and Ubiquitination Following Mechanical Stress-Induced Vascular Injury. Am J
Respir Crit Care Med, 2011 (Epub ahead
of print).
# Lodolce JP, Kolodziej LE, Rhee L,
Kariuki SN, Franek BS, McGreal NM,
Logsdon MF, Bartulis SJ, Perera MA,
Ellis NA, Adams EJ, Hanauer SB, Jolly M,
Niewold TB, Boone DL. African-derived
genetic polymorphisms in TNFAIP3
mediate risk for autoimmunity. J Immunol
184:7001-9, 2010.
Bishop BL, Lodolce JP, Kolodziej
LE, Boone DL, Tang WJ. The role of
anthrolysin O in gut epithelial barrier
disruption during Bacillus anthracis
infection. Biochem Biophys Res Commun
394:254-9, 2010.
CHMURA, STEVEN, MD, PHD
# Nichols MA, Mell LK, Hasselle MD,
Karrison TG, MacDermed D, Meriwether
A, Witt ME, Weichselbaum RR, Chmura
SJ. Outcomes in black patients with early
breast cancer treated with breast conservation therapy. Int J Radiat Oncol Biol Phys
79:392-9, 2011.
# Mell LK, Jeong JH, Nichols MA, Polite
BN, Weichselbaum RR, Chmura SJ.
Predictors of competing mortality in early
breast cancer. Cancer 116:5365-73, 2010.
CONZEN, SUZANNE, MD
# Gehlert S, Murray A, Sohmer D,
McClintock M, Conzen S, Olopade
O. The importance of transdisciplinary
collaborations for understanding and
resolving health disparities. Soc Work
Public Health 25:408-22, 2010.
# Szmulewitz RZ, Chung E, Al-Ahmadie
H, Daniel S, Kocherginsky M, Razmaria
A, Zagaja GP, Brendler CB, Stadler
WM, Conzen SD. Serum/glucocorticoidregulated kinase 1 expression in primary
human prostate cancers. Prostate, 2011
(Epub ahead of print).
Melhem-Bertrandt A, Chavez-Macgregor
M, Lei X, Brown EN, Lee RT, MericBernstam F, Sood AK, Conzen SD,
Hortobagyi
GN,
Gonzalez-Angulo
AM. Beta-blocker use is associated with
improved relapse-free survival in patients
with triple-negative breast cancer. J Clin
Oncol 29:2645-52, 2011. PMC3139371
Rizvi SA, Liu S, Chen Z, Skau C, Pytynia
M, Kovar DR, Chmura SJ, Kozmin SA.
Rationally simplified bistramide analog
reversibly targets actin polymerization and
inhibits cancer progression in vitro and in
vivo. J Am Chem Soc 132:7288-90, 2010.
# Jansen SA, Conzen SD, Fan X, Markiewicz E, Krausz T, Newstead GM,
Karczmar GS. In vivo MRI of early
stage mammary cancers and the normal
mouse mammary gland. NMR Biomed
24:880-7, 2011.
# Li J, Chaudhary A, Chmura SJ, Pelizzari C, Rajh T, Wietholt C, Kurtoglu
M, Aydogan B. A novel functional CT
contrast agent for molecular imaging of
cancer. Phys Med Biol 55:4389-97, 2010.
DU, WEI, PHD
# Aydogan B, Li J, Rajh T, Chaudhary
A, Chmura SJ, Pelizzari C, Wietholt C,
Kurtoglu M, Redmond P. AuNP-DG:
22
deoxyglucose-labeled gold nanoparticles
as X-ray computed tomography contrast
agents for cancer imaging. Mol Imaging
Biol 12:463-7, 2010.
* # Li B, Wang CZ, He TC, Yuan CS,
Du W. Antioxidants potentiate American
ginseng-induced killing of colorectal
cancer cells. Cancer Lett 289:62-70, 2010.
PMC2824022
* # Li B, Zhao J, Wang CZ, Searle J, He
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MA, McCallion AS, Ovcharenko I.
Genome-wide identification of conserved regulatory function in diverged
sequences. Genome Res 21:1139-49, 2011.
PMC3129256
Sierra MI, Wright MH, Nash PD. AMSH
interacts with ESCRT-0 to regulate
the stability and trafficking of CXCR4.
J Biol Chem 285:13990-4004, 2010.
PMC2859561
Wright MH, Berlin I, Nash PD.
Regulation of endocytic sorting by
ESCRT-DUB-mediated deubiquitination.
Cell Biochem Biophys 60:39-46, 2011.
26
Gotea V, Visel A, Westlund JM, Nobrega
MA, Pennacchio LA, Ovcharenko I.
Homotypic clusters of transcription factor
binding sites are a key component of
human promoters and enhancers. Genome
Res 20:565-77, 2010. PMC2860159
Xiong W, Rebay I. Abelson tyrosine kinase
is required for Drosophila photoreceptor
morphogenesis and retinal epithelial patterning. Dev Dyn 240:1745-55, 2011.
REHMAN, JALEES, MD
# Archer SL, Marsboom G, Kim GH,
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JR, Gomberg-Maitland M, Thebaud
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cell proliferation and a new therapeutic
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PMC2914302
RINKER-SCHAEFFER,
CARRIE, PHD
# Szmulewitz RZ, Clark R, Lotan T, Otto
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Khan S, Taylor JL, Rinker-Schaeffer CW.
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ROIZMAN, BERNARD, SCD
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Kalamvoki M, Roizman B. Interwoven
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ROSNER, MARSHA, PHD
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ROUX, BENOIT, PHD
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SALGIA, RAVI, MD, PHD
# Kurzrock R, Sherman SI, Ball DW,
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# Kwak EL, Bang YJ, Camidge DR,
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# Mackinnon AC, Tretiakova M, Henderson L, Mehta RG, Yan BC, Joseph L,
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# Faoro L, Singleton PA, Cervantes GM,
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# Surati M, Robinson M, Nandi S, Faoro
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# Catenacci DV, Cervantes G, Yala S,
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Seiwert T, Sanicola M, Henderson L,
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SKAPEK, STEPHEN, MD
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Al-Tahan A, Sarkis O, Harajly M,
Baghdadi OK, Zibara K, Boulos F, Dighe
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Skapek SX, Saab R. Retinoic acid fails
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differentiation in rhabdomyosarcoma.
Pediatr Blood Cancer, 2011 (Epub ahead
of print).
Rodeberg DA, Garcia-Henriquez N, Lyden
ER, Davicioni E, Parham DM, Skapek SX,
Hayes-Jordan AA, Donaldson SS, Brown
KL, Triche TJ, Meyer WH, Hawkins DS.
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of regional lymph node disease in patients
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STALEY, JONATHAN, PHD
Koodathingal P, Novak T, Piccirilli JA,
Staley JP. The DEAH box ATPases Prp16
and Prp43 cooperate to proofread 5’ splice
site cleavage during pre-mRNA splicing.
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Mayas RM, Maita H, Semlow DR, Staley
JP. Spliceosome discards intermediates via
the DEAH box ATPase Prp43p. PNAS
107:10020-5, 2010. PMC2890470
UCCCC SCIENTIFIC REPORT 2010 – 2011
Yang S, Parisien M, Major F, Roux B.
RNA structure determination using SAXS
data. J Phys Chem B 114:10039-48, 2010.
# Tan YH, Krishnaswamy S, Nandi S,
Kanteti R, Vora S, Onel K, Hasina R, Lo
FY, El-Hashani E, Cervantes G, Robinson
M, Hsu HS, Kales SC, Lipkowitz S,
Karrison T, Sattler M, Vokes EE, Wang
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in MET and EGFR tyrosine kinases. PLoS
One 5:e8972, 2010. PMC2813301
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Molecular Mechanisms of Cancer
* Shemon AN, Heil GL, Granovsky AE,
Clark MM, McElheny D, Chimon A,
Rosner MR, Koide S. Characterization of
the Raf kinase inhibitory protein (RKIP)
binding pocket: NMR-based screening
identifies small-molecule ligands. PLoS
One 5:e10479, 2010. PMC2864760
# Loganathan S, Kanteti R, Siddiqui SS,
El-Hashani E, Tretiakova M, Vigneswaran
H, Cervantes G, Natarajan V, Husain
AN, Vokes EE, Kindler HL, Salgia R.
Role of protein kinase C beta and vascular
endothelial growth factor receptor in
malignant pleural mesothelioma: Therapeutic implications and the usefulness of
Caenorhabditis elegans model organism. J
Carcinog 10:4, 2011. PMC3049271
TANG, WEI-JEN, PHD
Guo Q, Manolopoulou M, Bian Y, Schilling AB, Tang WJ. Molecular basis for
the recognition and cleavages of IGF-II,
TGF-alpha, and amylin by human
insulin-degrading enzyme. J Mol Biol
395:430-43, 2010. PMC2813390
Ralat LA, Kalas V, Zheng Z, Goldman
RD, Sosnick TR, Tang WJ. Ubiquitin is a
novel substrate for human insulin-degrading enzyme. J Mol Biol 406:454-66, 2011.
PMC3064465
Ralat LA, Guo Q, Ren M, Funke T,
Dickey DM, Potter LR, Tang WJ.
Insulin-degrading enzyme modulates the
natriuretic peptide-mediated signaling
response. J Biol Chem 286:4670-9, 2011.
PMC3039328
27
Molecular Mechanisms of Cancer
UCCCC SCIENTIFIC REPORT 2010 – 2011 Ren M, Guo Q, Guo L, Lenz M, Qian F,
Koenen RR, Xu H, Schilling AB, Weber
C, Ye RD, Dinner AR, Tang WJ. Polymerization of MIP-1 chemokine (CCL3 and
CCL4) and clearance of MIP-1 by insulindegrading enzyme. EMBO J 29:3952-66,
2010. PMC3020635
Ivancic D, Katzman RB, Grimm G, Lee
G, Fryer J, Nusrat A, Turner JR, Barrett
TA. Epithelial NF-kappaB enhances
transmucosal fluid movement by altering
tight junction protein composition after
T cell activation. Am J Pathol 176:158-67,
2010. PMC2797878
TURNER, JERROLD, MD, PHD
VANDER GRIEND, DONALD, PHD
Raleigh DR, Boe DM, Yu D, Weber CR,
Marchiando AM, Bradford EM, Wang Y,
Wu L, Schneeberger EE, Shen L, Turner
JR. Occludin S408 phosphorylation regulates tight junction protein interactions
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Vander Griend DJ, D’Antonio J, Gurel
B, Antony L, Demarzo AM, Isaacs JT.
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receptor signaling drives the growth of
human prostate cancer initiating cells.
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* # Chen L, Park SM, Tumanov AV,
Hau A, Sawada K, Feig C, Turner JR, Fu
YX, Romero IL, Lengyel E, Peter ME.
CD95 promotes tumour growth. Nature
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Raleigh DR, Wang Y, Shen L, Turner JR.
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function. PNAS 107:8237-41, 2010.
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Marchiando AM, Shen L, Graham
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Tang Y, Clayburgh DR, Mittal N,
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28
D’Antonio JM, Vander Griend DJ,
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SL, Koochekpour S, Isaacs JT. Loss of
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WHITE, KEVIN, PHD
# Stoddart A, McNerney ME, Bartom E,
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# Godley LA, Cunningham J, Dolan ME,
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MM. An integrated genomic approach
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PMC2815565
Selected Major Grants and Awards
INVESTIGATOR
TITLE
PROJECT
START DATE
END DATE
TOTAL
ANNUAL
COST
6/15/2010
5/31/2014
7/1/2010
CLASS
FUNDING AGENCY
$481,585
R01
National Heart, Lung,
and Blood Institute
6/30/2015
$411,843
R01
National Institutes .
of Health
Connexons in cardiovcascular cell
communication
ERIC BEYER
Biology of lens intercellular
communication
SUZANNE
CONZEN
Identifying mechanisms linking stress
biology to human breast cancer
6/20/2011
4/30/2016
$319,238
R01
National Cancer
Institute
SUZANNE
CONZEN
The role of SGK1 in triple-negative
breast cancer resistance to treatment
9/30/2010
8/31/2012
$185,250
R21
National Cancer
Institute
WEI DU
A novel approach to target Rb .
mutant cancers
4/1/2011
3/31/2016
$319,238
R01
National Cancer
Institute
WEI DU
Specific killing of prostate cancers with
inactivated Rb pathway
3/1/2010
3/31/2013
$234,000
N/A
Department of
Defense
GEOFFREY
GREENE
Structure-function analysis of ER in the
presence of TSEC mixtures
8/31/2010
8/31/2011
$254,118
N/A
Pfizer, Inc.
GEOFFREY
GREENE
Multi-domain assembly of nuclear
estrogen receptors: structural .
insights into ER-positive breast .
cancer therapeutics
4/1/2011
3/31/2013
$236,334
N/A
Department of
Defense
BRUCE LAHN
Development of the replica barcode
selection assay
9/1/2010
8/31/2012
$234,000
R21
National Institutes .
of Health
BRUCE LAHN
Investigating the role of gene occlusion
in cellular aging
10/1/2010
9/30/2014
$234,000
N/A
The Ellison Medical
Foundation
DEBORAH
LANG
The role of PAX3 in melanoma
metastasis
7/1/2011
6/30/2015
$125,000
N/A
American Cancer
Society
ERNST
LENGYEL
Adaptation of an organotypic .
3 dimensional culture for highthroughput screening
7/1/2011
6/30/2012
$156,000
R21
National Institutes .
of Health
MILAN
MRKSICH
Nanomaterials for cancer diagnostics
and therapeutics
9/21/2010
7/31/2015
$157,104
N/A
National Cancer
Institute
MARSHA
ROSNER
tRNA as therapeutic agent of .
breast cancer
7/1/2010
7/31/2012
$214,499
N/A
Department of
Defense
MARSHA
ROSNER
tRNA and its activation targets .
as biomarkers and regulators of .
breast cancer
9/1/2010
8/31/2012
$206,374
N/A
Department of
Defense
RAVI SALGIA
Testing c-Met antibody and SMI efficacy
3/5/2010
9/4/2011
$112,099
N/A
Lilly, Eli & Company
RAVI SALGIA
The role of CXCR4 inhibition
in combination with cytotoxic
chemotherapy in lung cancer: .
pre-clinical modeling and proposed
clinical study
9/7/2010
9/6/2012
$105,000
N/A
Lilly, Eli & Company
RAVI SALGIA
Testing c-Met antibody and SMI efficacy
3/5/2010
9/4/2011
$112,099
N/A
Lilly, Eli & Company
STEPHEN
SKAPEK
Molecular targeting in nonrhabdomyosarcoma soft tissue sarcoma
7/1/2011
6/30/2013
$120,111
N/A
St. Baldrick's
Foundation
UCCCC SCIENTIFIC REPORT 2010 – 2011
ERIC BEYER
Molecular Mechanisms of Cancer
The Molecular Mechanisms of Cancer Program has a funding base of $22,314,658 in annual total costs (current as
of July 2011). This sum includes $7,260,372 in NCI funding and $11,077,184 in other NIH funding. Due to space
constraints, only selected new awards since January 1, 2010 of $100,000 or greater in annual total costs are listed here.
29
UCCCC SCIENTIFIC REPORT 2010 – 2011 Molecular Mechanisms of Cancer
HEMATOPOIESIS AND HEMATOLOGICAL MALIGNANCIES
PROGRAM LEADERS
Wendy Stock, MD
Professor of Medicine
30
Michael Thirman, MD
Associate Professor of
Medicine
HE HEMATOPOIESIS AND HEMATOLOGICAL MALIGNANCIES
Program focuses on the cytogenetic and molecular analysis of
hematological malignant diseases. The Program brings together
a collaborative group of 28 members spanning three academic
departments with an integrated focus on basic, translational,
and clinical research. Members of this program have successfully
identified genes involved in both normal hematopoiesis and the
pathogenesis of leukemias and lymphomas, and translated their
findings into novel molecularly targeted therapeutic approaches
for hematological malignancies.
в– в– Determine mechanisms of hematopoiesis;
в– в– Define molecular and genetic risk groups in leukemia
and lymphoma;
UCCCC SCIENTIFIC REPORT 2010 – 2011
M E M B E R S O F T H E H E M ATO P O I E S I S A N D H E M ATO LO G I C A L
M A L I G N A N C I E S P R O G R A M S E E K TO :
Hematopoiesis and Hematological Malignancies
T
в– в– Develop and characterize animal models of leukemia
and lymphoma; and
в– в– Develop novel risk-adapted clinical trials for
hematologic malignancies.
31
UCCCC SCIENTIFIC REPORT 2010 – 2011 Hematopoiesis and Hematological Malignancies
PROGRAM MEMBERSHIP†John Anastasi, MD
Associate Professor of Pathology
П†James Nachman, MD
Professor of Pediatrics
Andrew Artz, MD
Assistant Professor of Medicine
Olatoyosi Odenike, MD
Assistant Professor of Medicine
Beverly Baron, MD
Associate Professor of Pathology
Kenan Onel, MD, PhD
Associate Professor of Pediatrics
Jianjun Chen, PhD
Assistant Professor of Medicine
Janet Rowley, MD, DSc
Professor of Medicine
Kenneth Cohen, MD
Assistant Professor of Medicine
Dorothy Sipkins, MD, PhD
Assistant Professor of Medicine
John Cunningham, MBBCh, MSc
Professor of Pediatrics
Sonali Smith, MD
Associate Professor of Medicine
Jill de Jong, MD, PhD
Assistant Professor of Pediatrics
Wendy Stock, MD
Professor of Medicine
Lucy Godley, MD, PhD
Associate Professor of Medicine
Michael Thirman, MD
Associate Professor of Medicine
Fotini Gounari, PhD, DSc
Assistant Professor of Medicine
П†Koen van Besien, MD
Professor of Medicine
Sandeep Gurbuxani, MBBS, PhD
Assistant Professor of Pathology
James Vardiman, MD
Professor of Pathology
Barbara Kee, PhD
Associate Professor of Pathology
Amittha Wickrema, PhD
Associate Professor of Medicine
Richard Larson, MD
Professor of Medicine
П†Yanming Zhang, MD
Assistant Professor of Medicine
Michelle Le Beau, PhD
Professor of Medicine
Todd Zimmerman, MD
Associate Professor of Medicine
Susana Marino, MD, PhD
Associate Professor of Pathology
Jennifer McNeer, MD
Assistant Professor of Pediatrics
†  Reflects all Program membership during 2010-2011 
φ  Individuals who are no longer at the UCCCC
32
Program Highlights††Due to space constraints, only a small representative sample of Program highlights is presented here.
MIR-17-92 MAY SERVE AS A
THERAPEUTIC TARGET IN MLLREARRANGED ACUTE LEUKEMIA
(INTRAPROGRAMMATIC)
TEMSIROLIMUS SHOWS
ACTIVITY IN NON-MANTLE
CELL NON-HODGKIN
LYMPHOMA SUBTYPES (INTRA/
INTERPROGRAMMATIC)
Although the rapamycin (mTOR)
pathway is a validated target in
mantle cell lymphoma, it has not been
extensively evaluated in other lymphomas. In collaboration with Dr.
Koen van Besien, Pharmacogenomics and Experimental Therapeutics
Program members Drs. Theodore
Karrison and Everett Vokes, Sonali
Smith, MD, conducted a phase II
trial to examine the response rate
of temsirolimus in patients with
relapsed aggressive and indolent
lymphomas. Temsirolimus, a water
soluble rapalog, is currently approved
for the treatment of metastatic renal
cell carcinoma. Patients with diffuse
large B-cell lymphoma (DLBCL) or
transformed follicular lymphoma
showed an overall and complete
response rate of 28.1% and 12.5%,
respectively, while patients with follicular lymphoma showed rates of
53.8% and 25.6%, respectively, with
mild toxicity. These results support
further evaluation of the mTOR
pathway as a therapeutic target in
these diseases. (Smith et al., J Clin
Oncol 28:4740-6, 2010)
UCCCC SCIENTIFIC REPORT 2010 – 2011
The microRNA (miR)-17-92 cluster
is frequently overexpressed in mixed
lineage leukemia (MLL)-rearranged
acute leukemias. Jianjun Chen,
PhD, and colleagues including
Drs. Michael Thirman and Janet
Rowley, demonstrated that MLL
fusion proteins exhibit stronger
direct binding to the miR-17-92
locus than wild-type MLL. Forced
expression of the miR-17-92 cluster
significantly increased the tertiary
colony formation capacity of normal
mouse bone marrow progenitor
cells, and cooperated with MLL
fusion proteins in transforming these
cells. The investigators also identified over 360 potential miR-17-92
target genes, which are significantly
enriched during cell differentiation,
hematopoiesis, apoptosis, and the
cell cycle. These results indicate that
miR-17-92 may play an essential role
in the development of MLL-associated leukemias, and suggest that this
cluster may serve as a potential target
for therapeutic intervention. (Mi et
al., PNAS 107:3710-5, 2010)
kowitz (Molecular Mechanisms of
Cancer Program), constructed transgenic mice expressing DNMT3B7,
a truncated DNMT3B isoform
commonly found in cancer cells,
to determine its effect on DNA
methylation. DNMT3B7 transgenic
mice exhibited altered embryonic
development including lymphopenia. When bred with EОј-Myc
transgenic mice, DNMT3B7 expression accelerated lymphomagenesis,
increased global DNA methylation,
and led to increased chromosomal
rearrangements. These data suggest
that truncated DNMT3B isoforms
can contribute to the redistribution
of DNA methylation that occurs
in cancer. (Shah et al., Cancer Res
70:5840-50, 2010)
Hematopoiesis and Hematological Malignancies
Publications
DNMT3B7 DISRUPTS
EMBRYONIC DEVELOPMENT
AND ACCELERATES
LYMPHOMAGENESIS (INTRA/
INTERPROGRAMMATIC)
Mechanisms by which cancer cells
acquire epigenetic changes, including abnormal methylation patterns,
are not well understood. Cancer cells
commonly express aberrant DNA
methyltransferase 3B transcripts.
Lucy Godley, MD, PhD, and colleagues including Drs. Michelle Le
Beau, John Anastasi, and Ivan Mos-
33
Hematopoiesis and Hematological Malignancies
UCCCC SCIENTIFIC REPORT 2010 – 2011 ARSENIC TRIOXIDE IMPROVES
SURVIVAL FOR ADULTS WITH
APL (INTRAPROGRAMMATIC)
Arsenic trioxide is an effective treatment for patients with relapsed acute
promyelocytic leukemia (APL). In a
randomized phase III trial, Richard
Larson, MD, and Wendy Stock,
MD, examined the efficacy of arsenic
trioxide consolidation in 481 patients
with APL in first remission. Eventfree survival and disease-free survival
were significantly improved for
patients assigned to arsenic trioxide
consolidation (80% and 90%,
respectively) compared to patients
assigned to standard consolidation
therapy (63% and 70%, respectively)
at 3 years. These data demonstrate
that the addition of arsenic trioxide
consolidation to standard induction and consolidation therapy
significantly improves event-free and
disease-free survival in adults with
newly diagnosed APL. (Powell et al.,
Blood 116:3751-7, 2010)
HIGH-DOSE CYTARABINE/
MITOXANTRONE FOLLOWED
BY HEMATOPOIETIC STEM
CELL TRANSPLANT IS A NEW
TREATMENT APPROACH
FOR T-MN (INTRA/
INTERPROGRAMMATIC)
A standard remission induction
and post-remission therapy for
patients with therapy-related myeloid
neoplasms (t-MN) does not exist.
Lucy Godley, MD, PhD, and
Richard Larson, MD, along with
Hematopoiesis and Hematological
Malignancies Program members
including Drs. Odenike, Artz, van
Besien, Zhang, Le Beau, and Stock,
and Dr. Christopher Daugherty
(Pharmacogenomics and Experimental Therapeutics Program), developed
a uniform prospective treatment
approach for patients with t-MN.
Using a single induction regimen of
high-dose cytarabine and mitoxan
34
trone, followed by hematopoietic
cell transplant whenever possible,
the investigators observed a complete
remission rate of 66%, partial
remission rate of 16%, and overall
response rate of 82%. Furthermore,
autologous stem cells that provided
durable and adequate graft function
were collected from selected patients
in remission from t-MN. The overall
approach was well-tolerated and
efficacious, even in older patients and
those with comorbidities, allowing
support for curative treatment strategies. (Godley et al., Leuk Lymphoma
51:995-1006, 2010)
VARIANTS AT 6Q21 IMPLICATE
PRDM1 IN THE ETIOLOGY
OF THERAPY-INDUCED
SECOND MALIGNANCIES
AFTER HODGKIN LYMPHOMA
(INTERPROGRAMMATIC)
Kenan Onel, MD, PhD, along with
Drs. R. Stephanie Huang (Pharmacogenomics and Experimental
Therapeutics Program), and Olufunmilayo Olopade (Cancer Prevention
and Control Program), discovered
two genetic variations on chromosome band 6q21 that can predict the
risk for developing secondary cancers
in pediatric patients undergoing radiation therapy for Hodgkin lymphoma.
Hematopoiesis and Hematological Malignancies
UCCCC SCIENTIFIC REPORT 2010 – 2011
Nearly 20% of these patients develop
secondary cancers within 30 years
of treatment. Dr. Onel performed
a genome-wide association study
and found that secondary cancers
were strongly associated with genetic
variations resulting in decreased
expression of PRDM1 gene and
impaired induction of PRDM1 after
radiation exposure. These findings
indicate a role for PRDM1 as a
radiation-responsive tumor suppressor
and will facilitate the understanding
of secondary tumor development in
cancer patients treated with radia-
tion therapy. (Best et al., Nat Med
17:941-3, 2011)
Grants
NUCLEAR ARCHITECTURE
OF LEUKEMIA STEM CELLS
FACILITATES GENETIC ANALYSIS
OF T-AML
Through funding from the Cancer
Research Foundation (CRF), John
Cunningham, MBBCh, MSc, is
exploring the nuclear architecture
of therapy-related acute myeloid
leukemia (t-AML) stem cells and
determining whether it contributes
to the initiation and progression of
leukemia as well as the resistance of
leukemic stem cells to chemotherapy.
By analyzing the distribution and
modification of histones, a map
of gene regulatory regions in both
normal leukemic stem cells is being
developed. These efforts will enhance
the ability to analyze complex gene
regulatory networks that regulate
t-AML and facilitate the identification of novel therapeutic targets.
35
Hematopoiesis and Hematological Malignancies
UCCCC SCIENTIFIC REPORT 2010 – 2011 36
THE MIR-17-92 CLUSTER
ENHANCES ACUTE MYELOID
LEUKEMIA
A cluster of microRNAs (miRNAs),
the mir-17-92, contains seven
miRNAs that are highly expressed
in malignant lymphomas and frequently overexpressed in various
acute leukemias. Jianjun Chen,
PhD, through R01 funding from the
National Cancer Institute, is investigating the mechanisms by which
miRNAs in this cluster may regulate
the proliferation and differentiation
of hematopoietic progenitor cells.
These studies will facilitate the
identification of target genes that
contribute towards leukemogenesis.
EFFORTS UNDER WAY TO
IDENTIFY FUSION TRANSCRIPTS
IN LEUKEMIA
Structural aberrations in the cancer
genome are used as genetic markers
for diagnosis, treatment, and prognosis. Janet Rowley, MD, DSc, and
colleagues from Northshore University Health System and The University
of Texas were awarded an RC1 grant
from the National Cancer Institute
to perform a systematic analysis to
identify fusion transcripts and their
chromosomal structural aberrations
in acute myeloid leukemia (AML).
The study will allow the identification of new candidate genes involved
in AML as well as genetic markers
for improved clinical diagnosis
and treatment.
Featured Faculty Profiles††Due to space constraints, only a small representative sample of Program members is presented here.
Assistant Professor of Medicine
The goal of Dr. Andrew Artz’s research is to improve outcomes among older
adults with hematologic disorders by using individualized treatment strategies.
A second area of active investigation aims to characterize otherwise unexplained anemia to
identify patients who may harbor an occult or impending hematologic malignancy. Dr. Artz
has established a unique Geriatric Anemia Clinic that allows clinicians to carefully phenotype
patients, provide samples for a biorepository, and perform interventional trials. He has recently
reported that approximately 7.5% of older anemic adults have an underlying hematologic malignancy, and that myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) account for
half of these malignancies.1 Moreover, approximately 15% of the remaining anemia patients have
blood or marrow findings suggesting a precursor lesion to MDS (i.e., early MDS). Along with
his collaborator, Amittha Wickrema, PhD, Dr. Artz is searching for biomarkers to establish new
diagnostic tools for earlier diagnosis and treatment of MDS or AML. Finally, through an NIHfunded consortium, they have initiated a series of clinical trials to study unexplained anemia in
the elderly. Interventions aimed at early MDS will be tested in the near future.
UCCCC SCIENTIFIC REPORT 2010 – 2011
Allogeneic hematopoietic cell transplantation (HCT) remains the major
modality to eradicate high-risk and relapsed hematologic malignancies, but
its extension to older adults is limited because of transplant-related morbidity
and mortality. Dr. Artz’s research employs established tools (e.g., biomarkers,
geriatric assessment) to detect subtle health impairments in elderly patients
as novel predictors of acute toxicities after curative intent transplantation
for adults 50 to 75 years of age. His research demonstrates that the presence
of comorbid conditions and mild functional limitations are predicative of
worse tolerance. He and his colleagues have also reported that pre-transplant
elevated c-reactive protein (CRP) and possibly IL-6 track closely with
transplant-associated morbidity and mortality. Dr. Artz and his colleagues
have recently completed a prospective comprehensive geriatric assessment
Andrew Artz, MD
(CGA) of 140 adults (50 years of age or older) undergoing HCT. Their preliminary data reveal a wide range of limitations by CGA among patients with
good performance status. In addition, self-reported measures of quality of life strongly predict
transplant-related mortality independent of standard measures while evidence of frailty, adjusted
for disease status, tracked with greater relapse. Ongoing work will delineate the essential novel
prognostic factors for tolerance and study interventions targeted at patients at high risk for poor
tolerance and/or specific limitations.
Hematopoiesis and Hematological Malignancies
ANDREW ARTZ, MD
Artz AS, Thirman MJ. Unexplained anemia predominates despite an intensive evaluation in a racially diverse cohort of older adults
from a referral anemia clinic. J Gerontol A Biol Sci Med Sci 66:925-932, 2011.
1
37
Hematopoiesis and Hematological Malignancies
UCCCC SCIENTIFIC REPORT 2010 – 2011 LUCY GODLEY, MD, PHD
Associate Professor of Medicine
The goal of Dr. Lucy Godley’s research is to understand the molecular basis
of bone marrow malignancies. The specific aims of her research are to: 1)
understand the pathways that lead to altered patterns of DNA methylation/
hydroxymethylation in human bone marrow cancers; and 2) learn what predisposes patients with inherited RUNX1 mutations to develop leukemia. By
understanding the molecular basis of these pathways, her hope is to develop
rational therapies that will be more effective and less toxic for patients.
Epigenetic changes, including modifications of histone proteins and cytosine
bases in DNA, alter chromatin structure to regulate gene transcription.
Cancer cells are characterized by abnormal patterns of DNA methylation/
hydroxymethylation. Work in Dr. Godley’s laboratory focuses on elucidating mechanisms that control these modifications within cancer cells. She has
shown that cancer cells exhibit aberrant splicing of the DNMT3B gene, producing DNMT3B transcripts containing premature stop codons that encode
Lucy Godley, MD, PhD
truncated proteins lacking the catalytic domain. Using mass spectrometry
and a chemical labeling method developed in Dr. Chuan He’s laboratory
(Pharmacogenomics and Experimental Therapeutics Program), her laboratory has detected low
levels of hydroxymethylcytosine in several subtypes of acute myeloid leukemia (AML), including
those with TET2 or IDH1/2 mutations. They have also observed that treatment of leukemia cells
with so-called “hypomethylating agents” actually increases levels of hydroxymethylation. As a
result, they are testing whether this effect could drive the clinical efficacy of these drugs.
In recent findings, Dr. Godley demonstrated that a truncated DNMT3B isoform found in human
cancer cells can alter Myc-driven tumorigenesis.1 Her laboratory has shown that other tumors
driven by Myc or MYC family members are very sensitive to DNA methylation. Dr. Godley
and her collaborators have also demonstrated that AMLs with TET2 or IDH1/2 mutations have
increased levels of DNA methylation.2 They have expanded their findings and shown that these
leukemias also have less hydroxymethylation. Current work is focused on the identification of
affected genes.
Shah MY, Vasanthakumar A, Barnes NY, Figueroa ME, Kamp A, Hendrick C, Ostler KR, Davis EM, Lin S, Anastasi J, Le Beau
MM, Moskowitz IP, Melnick A, Pytel P, Godley LA. DNMT3B7, a truncated DNMT3B isoform expressed in human tumors,
disrupts embryonic development and accelerates lymphomagenesis. Cancer Res 70:5840-5850, 2010.
1
Figueroa ME, Abdel-Wahab O, Lu C, Ward PS, Patel J, Shih A, Li Y, Bhagwat N, Vasanthakumar A, Fernandez HF, Tallman
MS, Sun Z, Wolniak K, Peeters JK, Liu W, Choe SE, Fantin VR, Paietta E, Löwenberg B, Licht JD, Godley LA, Delwel R, Valk PJ,
Thompson CB, Levine RL, Melnick A. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2
function, and impair hematopoietic differentiation. Cancer Cell 18:553-567, 2010.
2
38
Assistant Professor of Pathology
Dr. Sandeep Gurbuxani’s long-standing interest is to uncover the mechanisms of resistance to chemotherapy-induced cell death in acute leukemias.
Specifically, his laboratory is investigating how glucocorticoids induce cell
death in acute lymphoblastic leukemia (ALL). Synthetic glucocorticoids,
such as dexamethasone and prednisone, have been used for treating ALL for
over 5 decades. Indeed, sensitivity to glucocorticoids is the most important
predictor of treatment outcome in ALL patients. In spite of the extensive use
and crucial impact on outcome, the mechanism of glucocorticoid-induced
cell death is poorly understood. A lack of understanding of these mechanisms
has also hampered the capacity to overcome the phenomenon of resistance
to glucocorticoid-mediated cell death in a small but significant minority of
de novo ALL patients as well as in the vast majority of ALL patients at the
time of relapse.
Dr. Gurbuxani’s laboratory is using two strategies to identify the mechanisms of glucocorticoidinduced cell death. Both of these approaches are influenced by current knowledge about the
physiological role of endogenous glucocorticoids. Since glucocorticoids mediate their effects by a
GR-mediated transcriptional program, Dr. Gurbuxani is determining whether the activated GR
influences the transcription of a unique set of genes in ALL cells. In a second set of experiments,
he is determining the effect of glucocorticoids on the metabolism of ALL cells. The cell death
observed in ALL cells may possibly be a consequence of catastrophic perturbations in cellular
metabolism that result in depletion of essential housekeeping molecules. In the long run, Dr.
Gurbuxani expects to exploit the information obtained from these experiments for developing
targeted therapy for ALL that is refractory to glucocorticoid-mediated cell death.
UCCCC SCIENTIFIC REPORT 2010 – 2011
Of note, the phenomenon of cell death in response to glucocorticoid exposure
Sandeep Gurbuxani, MBBS, PhD
is observed only in limited tissue types, the most important being immature
lymphoid cells. Interestingly, endogenous glucocorticoids secreted by the
adrenal cortex control a myriad of cellular functions, most notably glucose metabolism. Glucocorticoids mediate their effects by binding to the glucocorticoid receptor (GR), a transcription
factor of the nuclear receptor family. Once activated, the GR generates a response that involves
both transactivation and transrepression.
Hematopoiesis and Hematological Malignancies
SANDEEP GURBUXANI, MBBS, PHD
39
Hematopoiesis and Hematological Malignancies
AMITTHA WICKREMA, PHD
Associate Professor of Medicine
Dr. Amittha Wickrema’s research program focuses on the molecular
mechanisms underlying normal and malignant hematopoiesis. Specifically,
he studies the epigenetic, transcriptional, and post-translational regulatory
circuits that guide blood stem cells in the commitment and terminal differentiation to red blood cells.
UCCCC SCIENTIFIC REPORT 2010 – 2011 Amittha Wickrema, PhD
Over the years, Dr. Wickrema’s laboratory has developed a unique human
cellular model for studying the commitment, proliferation, and terminal differentiation of blood stem cells to erythroid progenitors, erythroblasts, and
reticulocytes. This model is unique because it recapitulates in vitro the normal
program driven by specific cytokines and a stringent feeding regimen. They
have utilized this primary human model to define signaling pathways and
cytokine requirements critical for cell survival, proliferation, and terminal
differentiation. These studies not only revealed the molecular basis of human
erythroblast differentiation, but also identified the pathways essential for
enucleation.1-3
Most recently, Dr. Wickrema’s laboratory uncovered osteopontin (OPN), a cytokine associated with
bone development, to be involved in the regulation of erythroblast actin cytoskeleton.4 This initial
finding led them to investigate the role of OPN in the regulation of mature red blood cell homeostasis under normal and pathologic conditions. Serum OPN levels are highly elevated in many clinical
conditions, including cancer and sickle cell disease. Current studies include investigation of the
role played by OPN in the regulation of mature red blood cell deformability and metabolic flux,
which are key characteristics for the long-term survival of red blood cells. These studies also include
examination of the impact of elevated OPN on oxidative stress in sickle red blood cells.
Dr. Wickrema’s second area of investigation focuses on adaptation of the human erythroblast
model to culture and force differentiation of myelodysplastic stem/erythroid progenitors as a
tool for early diagnosis as well as for studying candidate genes associated with the pathogenesis
of myelodysplastic syndromes (MDS). MDS represents a group of pre-malignant diseases that
quickly proceeds to becoming malignant. Most patients with MDS are initially diagnosed with
anemia, and approximately 25% of patients with unexplained anemia develop MDS.
Current efforts in the laboratory include identification of genetic aberrations in very early MDS
stem/erythroid cells and the functional consequence of these aberrations in disrupting either commitment survival and/or terminal differentiation, including globin synthesis and enucleation. This
project is being carried out in collaboration with Drs. Andrew Artz and Amit Verma, a physician
scientist and long-time collaborator at Albert Einstein University.
Wickrema A, Uddin S, Sharma A, Chen F, Alsayed Y, Ahmad S, Sawyer ST, Krystal G, Yi T, Nishada K, Hibi M, Hirano T,
Platanias LC. Engagement of Gab1 and Gab2 in erythropoietin signaling. J Biol Chem 274:24469-24474, 1999.
1
Mahmud DL, G-Amlak M, Deb DK, Platanias LC, Uddin S, Wickrema A. Phosphorylation of forkhead transcription factors
by erythropoietin and stem cell factor prevents acetylation and their interaction with coactivator p300 in erythroid progenitor cells.
Oncogene 21:1556-1562, 2002.
2
3 Uddin S, Ah-Kang J, Ulaszek J, Mahmud D, Wickrema A. Differentiation stage-specific activation of p38 mitogen-activated protein
kinase isoforms in primary human erythroid cells. PNAS 101:147-512, 2004.
Kang JA, Zhou Y, Weis TL, Liu H, Ulaszek J, Satgurunathan N, Zhou L, van Besien K, Crispino J, Verma A, Low PS, Wickrema A.
Osteopontin regulates actin cytoskeleton and contributes to cell proliferation in primary erythroblasts. J Biol Chem 283:6997-7006, 2008.
4
40
Hematopoiesis and Hematological Malignancies
MICHAEL THIRMAN, MD
Associate Professor of Medicine
Dr. Michael Thirman’s laboratory focuses on the role of MLL and its partner
proteins in the development of acute leukemia. He has cloned the ELL gene and
its interacting factors, EAF1 and EAF2. Using model systems, Dr. Thirman’s
laboratory analyzes the pathways that mediate leukemogenesis and seeks to
translate this knowledge into the development of novel treatment strategies.
MLL encodes a histone methyltransferase that is critical in maintaining gene
expression during embryonic development and hematopoiesis. 11q23 translocations result in the formation of chimeric MLL fusion proteins that act as
potent drivers of acute leukemia. However, it remains unclear what portion of
the leukemic genome is under the direct control of MLL fusions. Independent
expression profiling studies on primary patient samples and cellular leukemic
models have revealed a smaller number of genes (в€ј100) which are differentially expressed in MLL-rearranged leukemias. Collectively, these studies do
not provide a clear picture regarding what portion of the genome is directly
controlled by MLL fusion proteins.
Michael Thirman, MD
UCCCC SCIENTIFIC REPORT 2010 – 2011
To address these important issues, Dr. Thirman’s laboratory undertook two parallel strategies,
including mapping MLL binding in multiple human leukemia patient-derived cell lines, and
a combined location and expression profiling analysis in an MLL-ENL–inducible system.1 By
comparing patient-derived leukemic cell lines, they observed that MLL fusion-bound genes are
a small subset recognized by wild-type MLL. In an inducible MLL-ENL model, MLL fusion
protein binding and changes in H3K79 methylation are limited to a specific portion of the
genome, whereas wild-type MLL distributes to a much larger set of gene loci. Surprisingly, among
223 MLL-ENL-bound genes, only 12 demonstrate a significant increase in mRNA expression
on induction of the fusion protein. Among target genes whose expression is strongly influenced
by MLL-ENL, Dr. Thirman’s laboratory has identified key developmental regulators that potentially contribute to the development of MLL-associated leukemia. These include HOXA9 and
its cofactor, MEIS1, which have previously been identified as targets of MLL fusion genes. In
addition, Dr. Thirman has identified the transcription factors EYA1, SIX1, and SIX4 as direct
MLL-ENL targets. EYA proteins form heterodimers with members of the SIX protein family.
They found that Eya1 has the capacity to immortalize hematopoietic progenitor cells in vitro
and collaborates with Six1 in hematopoietic transformation assays. Altogether, the data suggest
that MLL fusions contribute to the development of acute leukemia through direct activation of
a small set of target genes.
1 Wang Q, Wu G, Mi S, He F, Wu J, Dong J, Luo RT, Mattison R, Kaberlein J, Prabhakar S, Ji H, Thirman MJ.
MLL fusion proteins
preferentially regulate a subset of wild type MLL target genes in the leukemic genome. Blood 117:6895-9605, 2011. 41
Hematopoiesis and Hematological Malignancies
UCCCC SCIENTIFIC REPORT 2010 – 2011 RICHARD LARSON, MD
Professor of Medicine
The goal of Dr. Richard Larson’s research program is to understand the
determinants of response to treatment in patients with acute leukemia. The
methods include prospective clinical trials, evaluation of novel therapeutic
agents, and correlation of cytogenetic and molecular markers that identify
biologically distinct subsets of leukemia.
A primary focus of Dr. Larson’s work has been to understand the etiology of
therapy-related leukemia. It is now well-recognized that leukemia sometimes
occurs as a therapy-related myeloid neoplasm (t-MN) in patients who have
previously received cytotoxic therapy or ionizing radiation therapy (RT).
The exact mechanism of the leukemogenic transformation remains to be
determined. This disorder arises as a direct consequence of mutational events
induced by the primary treatment. The outcomes for these patients have been
historically poor compared to people who develop acute myeloid leukemia
(AML) de novo. Currently comprising 10%-20% of all cases of AML, t-MN
Richard Larson, MD
is relatively resistant to conventional leukemia therapies and is associated
with short survival times. Median life expectancy from diagnosis is about
8-10 months in most cases.1
Although the spectrum of cytogenetic abnormalities in t-AML is similar to AML de novo, the
frequency of unfavorable cytogenetics, such as a complex karyotype or deletion or loss of chromosomes 5 and/or 7, is considerably higher in t-MN. Two distinct groups of patients with t-MN
have been described. The more common subtype, seen in about 75% of patients, typically occurs
5-7 years after first exposure to alkylating agents or radiation, is often preceded by a myelodysplastic syndrome, and is frequently accompanied by clonal cytogenetic abnormalities such as
the loss of all or part of chromosomes 5 or 7. Mutations of the TP53 tumor suppressor gene are
also common. The risk is related to total cumulative exposure over time to alkylating agents. In
contrast, among individuals who develop t-AML after treatment with topoisomerase II inhibitors,
the latency period to the development of t-AML is often only 1-3 years, antecedent MDS is rare,
and gene rearrangements involving MLL at 11q23 or RUNX1/AML1 at 21q22 are common. It is
now well-recognized that acute promyelocytic leukemia (APL) and other subtypes of AML with
balanced translocations sometimes occur as a t-MN in patients who have previously received
cytotoxic therapy or ionizing radiation therapy. In general, t-MN patients should be encouraged
to participate in prospective clinical trials that are appropriately designed for other AML patients
with similar cytogenetic abnormalities. Patients who have an HLA-matched donor should be
considered for allogeneic hematopoietic cell transplantation, although patients with favorable
karyotypes such as t(15;17) and inv(16) may do well with conventional intensive chemotherapy.2,3
1 Larson RA, Le Beau MM. Prognosis and therapy of therapy-related acute promyelocytic leukemia and other “good risk” acute myeloid
leukemias. Mediterr J Hematol Infect Dis 3: e2011032, 2011. 2
Larson, RA. Therapy-related myeloid neoplasms. Haematologica 94:454-459, 2009.
Godley LA, Njiaju UO, Green M, Weiner H, Lin S, Odenike O, Rich ES, Artz A, Van Besien K, Daugherty CK, Zhang Y, Le Beau
MM, Stock W, Larson RA. Treatment of therapy-related myeloid neoplasms with high-dose cytarabine/mitoxantrone followed by
hematopoietic stem cell transplant. Leuk Lymphoma 5:995-1006, 2010.
3
42
Selected Publications
* : Intraprogrammatic Collaboration
# : Interprogrammatic Collaboration
* Stoddart A, Tennant TR, Fernald AA,
Anastasi J, Brodsky FM, Le Beau MM.
The clathrin-binding domain of CALMAF10 alters the phenotype of myeloid
neoplasms in mice. Oncogene 2011
(Epub ahead of print).
* # Shah MY, Vasanthakumar A, Barnes
NY, Figueroa ME, Kamp A, Hendrick
C, Ostler KR, Davis EM, Lin S, Anastasi
J, Le Beau MM, Moskowitz IP, Melnick
A, Pytel P, Godley LA. DNMT3B7, a
truncated DNMT3B isoform expressed
in human tumors, disrupts embryonic
development and accelerates lymphomagenesis. Cancer Res 70:5840-50, 2010.
PMC2905468
* Smith SM, Anastasi J, Cohen KS,
Godley LA. The impact of MYC expression in lymphoma biology: beyond
Burkitt lymphoma. Blood Cells Mol Dis
45:317-23, 2010.
ARTZ, ANDREW, MD
* Locke FL, Artz A, Rich E, Zhang Y,
van Besien K, Stock W. Feasibility of clofarabine cytoreduction before allogeneic
transplant conditioning for refractory
AML. Bone Marrow Transplant 45:16928, 2010.
* # Godley LA, Njiaju UO, Green M,
Weiner H, Lin S, Odenike O, Rich ES,
Artz A, Van Besien K, Daugherty CK,
Zhang Y, Le Beau MM, Stock W, Larson
RA. Treatment of therapy-related myeloid
neoplasms with high-dose cytarabine/
mitoxantrone followed by hematopoietic
stem cell transplant. Leuk Lymphoma
51:995-1006, 2010.
* Artz AS, Thirman MJ. Unexplained
anemia predominates despite an intensive
evaluation in a racially diverse cohort
of older adults from a referral anemia
clinic. J Gerontol A Biol Sci Med Sci
66:925-32, 2011.
* # O’Donnell PH, Artz AS, Undevia SD,
Pai RK, Del Cerro P, Horowitz S, Godley
LA, Hart J, Innocenti F, Larson RA,
Odenike OM, Stock W, Van Besien K.
Phase I study of dose-escalated busulfan
with fludarabine and alemtuzumab as
conditioning for allogeneic hematopoietic
stem cell transplant: reduced clearance at
high doses and occurrence of late sinusoidal obstruction syndrome/veno-occlusive
disease. Leuk Lymphoma 51:2240-9, 2010.
Hurria A, Cirrincione CT, Muss HB,
Kornblith AB, Barry W, Artz AS, Schmieder L, Ansari R, Tew WP, Weckstein D,
Kirshner J, Togawa K, Hansen K, Katheria
V, Stone R, Galinsky I, Postiglione J,
Cohen HJ. Implementing a geriatric
assessment in cooperative group clinical
cancer trials: CALGB 360401. J Clin
Oncol 29:1290-6, 2011. PMC3083997
* van Besien K, Kenkre V, Artz AS. T-celldepleted reduced-intensity conditioning
transplantation for lymphoma: do donor
lymphocyte infusions really matter? J Clin
Oncol 29:e243, 2011.
Liu H, Artz AS. Reduction of imatinib
absorption after gastric bypass surgery.
Leuk Lymphoma 52:310-3, 2011.
BARON, BEVERLY, MD
Armand P, Kim HT, Zhang MJ, Perez
WS, Dal Cin PS, Klumpp TR, Waller EK,
Litzow MR, Liesveld JL, Lazarus HM,
Artz AS, Gupta V, Savani BN, McCarthy
PL, Cahn JY, Schouten HC, Finke J,
Ball ED, Aljurf MD, Cutler CS, Rowe
* Baron BW, Hyjek E, Gladstone B,
Thirman MJ, Baron JM. PDCD2, a
protein whose expression is repressed by
BCL6, induces apoptosis in human cells
by activation of the caspase cascade. Blood
Cells Mol Dis 45:169-75, 2010.
CHEN, JIANJUN, PHD
Xiong Y, Li Z, Ji M, Tan AC, Bemis J,
Tse JV, Huang G, Park J, Ji C, Chen J,
Bemis LT, Bunting KD, Tse W. MIR29B
regulates expression of MLLT11 (AF1Q),
an MLL fusion partner, and low MIR29B
expression associates with adverse cytogenetics and poor overall survival in AML.
Br J Haematol 153:753-7, 2011.
Du W, Li J, Sipple J, Chen J, Pang Q.
Cytoplasmic FANCA-FANCC complex
interacts and stabilizes the cytoplasmdislocalized leukemic nucleophosmin
protein (NPMc). J Biol Chem 285:3743644, 2010. PMC2988349
* Mi S, Li Z, Chen P, He C, Cao D,
Elkahloun A, Lu J, Pelloso LA, Wunderlich M, Huang H, Luo RT, Sun M, He
M, Neilly MB, Zeleznik-Le NJ, Thirman
MJ, Mulloy JC, Liu PP, Rowley JD, Chen
J. Aberrant overexpression and function of
the miR-17-92 cluster in MLL-rearranged
acute leukemia. PNAS 107:3710-5, 2010.
PMC2840429
Wang Y, Li Z, He C, Wang D, Yuan X,
Chen J, Jin J. MicroRNAs expression
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mitoxantrone followed by hematopoietic
Slovak ML, Bedell V, Lew D, Albain KS,
Ellis GK, Livingston RB, Martino S,
Perez EA, Hortobagyi GN, Sher D, Stock
W. Screening for clonal hematopoiesis as
a predictive marker for development of
therapy-related myeloid neoplasia (t-MN)
following neoadjuvant therapy for breast
cancer: a Southwest Oncology Group
study (S0012). Breast Cancer Res Treat
119:391-8, 2010. PMC3024910
* Powell BL, Moser B, Stock W, Gallagher
RE, Willman CL, Stone RM, Rowe JM,
Coutre S, Feusner JH, Gregory J, Couban
S, Appelbaum FR, Tallman MS, Larson
RA. Arsenic trioxide improves event-free
and overall survival for adults with acute
promyelocytic leukemia: North American
Leukemia Intergroup Study C9710. Blood
116:3751-7, 2010. PMC2981533
* Locke FL, Artz A, Rich E, Zhang Y, van
Besien K, Stock W. Feasibility of clofarabine
cytoreduction before allogeneic transplant
conditioning for refractory AML. Bone
Marrow Transplant 45:1692-8, 2010.
Stock W. Adolescents and young adults
with acute lymphoblastic leukemia.
Hematology Am Soc Hematol Educ
Program 2010:21-9, 2010.
* # Kenkre VP, Horowitz S, Artz AS,
Liao C, Cohen KS, Godley LA, Kline JP,
Smith SM, Stock W, van Besien K. T-celldepleted allogeneic transplant without
donor leukocyte infusions results in excellent long-term survival in patients with
multiply relapsed Lymphoma. Predictors
for survival after transplant relapse. Leuk
Lymphoma 52:214-22, 2011.
* # Godley LA, Cunningham J, Dolan
ME, Huang RS, Gurbuxani S, McNerney
ME, Larson RA, Leong H, Lussier Y,
Onel K, Odenike O, Stock W, White KP,
Le Beau MM. An integrated genomic
approach to the assessment and treatment
of acute myeloid leukemia. Semin Oncol
38:215-24, 2011.
* # O’Donnell PH, Artz AS, Undevia SD,
Pai RK, Del Cerro P, Horowitz S, Godley
LA, Hart J, Innocenti F, Larson RA,
Odenike OM, Stock W, Van Besien K.
Phase I study of dose-escalated busulfan
with fludarabine and alemtuzumab as
conditioning for allogeneic hematopoietic
stem cell transplant: reduced clearance at
high doses and occurrence of late sinusoidal obstruction syndrome/veno-occlusive
disease. Leuk Lymphoma 51:2240-9, 2010.
THIRMAN, MICHAEL, MD
* Artz AS, Thirman MJ. Unexplained
anemia predominates despite an intensive
evaluation in a racially diverse cohort of
older adults from a referral anemia clinic.
J Gerontol A Biol Sci Med Sci 66:925-32,
2011.
Wang QF, Wu G, Mi S, He F, Wu J, Dong
J, Luo RT, Mattison R, Kaberlein JJ, Prabhakar S, Ji H, Thirman MJ. MLL fusion
proteins preferentially regulate a subset
of wild-type MLL target genes in the
leukemic genome. Blood 117:6895-905,
2011. PMC3128481
* Baron BW, Hyjek E, Gladstone B,
Thirman MJ, Baron JM. PDCD2, a
protein whose expression is repressed by
BCL6, induces apoptosis in human cells
by activation of the caspase cascade. Blood
Cells Mol Dis 45:169-75, 2010.
* Mi S, Li Z, Chen P, He C, Cao D,
Elkahloun A, Lu J, Pelloso LA, Wunderlich M, Huang H, Luo RT, Sun M, He
M, Neilly MB, Zeleznik-Le NJ, Thirman
MJ, Mulloy JC, Liu PP, Rowley JD, Chen
J. Aberrant overexpression and function of
the miR-17-92 cluster in MLL-rearranged
acute leukemia. PNAS 107:3710-5, 2010.
PMC2840429
VAN BESIEN, KOEN, MD
* van Besien K, Schouten V, Parsad S,
Smith S, Odenike O, Artz A. Allogeneic
stem cell transplantation in renal failure.
Engraftment and prolonged survival, but
high incidence of neurologic toxicity. Leuk
Lymphoma, 2011 (Epub ahead of print).
Greinix HT, van Besien K, Elmaagacli
AH, Hillen U, Grigg A, Knobler R, Parenti
D, Reddy V, Theunissen K, Michallet M,
Flowers ME. Progressive improvement in
cutaneous and extracutaneous chronic
graft-versus-host disease after a 24-week
course of extracorporeal photopheresisResults of a crossover randomized study.
Biol Blood Marrow Transplant, 2011
(Epub ahead of print).
UCCCC SCIENTIFIC REPORT 2010 – 2011
* Smith SM, Anastasi J, Cohen KS,
Godley LA. The impact of MYC expression in lymphoma biology: beyond Burkitt
lymphoma. Blood Cells Mol Dis 45:317-23,
2010.
stem cell transplant. Leuk Lymphoma
51:995-1006, 2010.
Hematopoiesis and Hematological Malignancies
Fowler N, Kahl BS, Lee P, Matous JV,
Cashen AF, Jacobs SA, Letzer J, Amin B,
Williams ME, Smith S, Saleh A, Rosen P,
Shi H, Parasuraman S, Cheson BD. Bortezomib, bendamustine, and rituximab in
patients with relapsed or refractory follicular
lymphoma: The phase II VERTICAL
Study. J Clin Oncol 29:3389-95, 2011.
* # O’Donnell PH, Artz AS, Undevia SD,
Pai RK, Del Cerro P, Horowitz S, Godley
LA, Hart J, Innocenti F, Larson RA,
Odenike OM, Stock W, Van Besien K.
Phase I study of dose-escalated busulfan
with fludarabine and alemtuzumab as
conditioning for allogeneic hematopoietic
stem cell transplant: reduced clearance at
high doses and occurrence of late sinusoidal obstruction syndrome/veno-occlusive
disease. Leuk Lymphoma 51:2240-9, 2010.
47
Hematopoiesis and Hematological Malignancies
UCCCC SCIENTIFIC REPORT 2010 – 2011 * # Kenkre VP, Horowitz S, Artz AS,
Liao C, Cohen KS, Godley LA, Kline JP,
Smith SM, Stock W, van Besien K. T-celldepleted allogeneic transplant without
donor leukocyte infusions results in excellent long-term survival in patients with
multiply relapsed lymphoma. Predictors
for survival after transplant relapse. Leuk
Lymphoma 52:214-22, 2011.
* Marino SR, Lin S, Maiers M, Haagenson M, Spellman S, Klein JP, Binkowski
TA, Lee SJ, van Besien K. Identification
by random forest method of HLA class I
amino acid substitutions associated with
lower survival at day 100 in unrelated
donor hematopoietic cell transplantation.
Bone Marrow Transplant, 2011 (Epub
ahead of print). PMC3128239
Shaughnessy PJ, Bolwell BJ, van Besien K,
Mistrik M, Grigg A, Dodds A, Prince HM,
Durrant S, Ilhan O, Parenti D, Gallo J, Foss
F, Apperley J, Zhang MJ, Horowitz MM,
Abhyankar S. Extracorporeal photopheresis
for the prevention of acute GVHD in
patients undergoing standard myeloablative
conditioning and allogeneic hematopoietic
stem cell transplantation. Bone Marrow
Transplant 45:1068-76, 2010.
* # Poire X, Kline J, Grinblatt D, Zimmerman T, Conner K, Muhs C, Gajewski T,
Van Besien K, Smith SM. Phase II study
of immunomodulation with granulocytemacrophage colony-stimulating factor,
interleukin-2, and rituximab following
autologous stem cell transplant in patients
with relapsed or refractory lymphomas.
Leuk Lymphoma 51:1241-50, 2010.
Martin PJ, Storer BE, Carpenter PA,
Couriel DR, Flowers ME, Gupta V, Hsu
JW, Jagasia M, Kitko CL, Maziarz RT,
Rowley SD, Shaughnessy PJ, van Besien
K, Weisdorf D, Lee SJ. Comparison
of short-term response and long-term
outcomes after initial systemic treatment
of chronic graft-versus-host disease. Biol
Blood Marrow Transplant 17:124-32,
2011. PMC2974028
VARDIMAN, JAMES, MD
Mesa RA, Green A, Barosi G, Verstovsek
S, Vardiman J, Gale RP. MPN-associated
myelofibrosis (MPN-MF). Leuk Res
35:12-3, 2011.
48
* Kolitz JE, George SL, Marcucci G, Vij R,
Powell BL, Allen SL, DeAngelo DJ, Shea
TC, Stock W, Baer MR, Hars V, Maharry
K, Hoke E, Vardiman JW, Bloomfield
CD, Larson RA. P-glycoprotein inhibition using valspodar (PSC-833) does not
improve outcomes for patients younger
than age 60 years with newly diagnosed
acute myeloid leukemia: Cancer and
Leukemia Group B study 19808. Blood
116:1413-21, 2010. PMC2938834
WICKREMA, AMITTHA, PHD
Wickrema A. Will cord blood stem cells
come to the rescue of keratinocyte growth
factor? Leuk Lymphoma 52:1423-4, 2011.
Zhou L, Opalinska J, Sohal D, Yu Y, Mo
Y, Bhagat T, Abdel-Wahab O, Fazzari M,
Figueroa M, Alencar C, Zhang J, Kambhampati S, Parmar S, Nischal S, Hueck
C, Suzuki M, Freidman E, Pellagatti A,
Boultwood J, Steidl U, Sauthararajah Y,
Yajnik V, McMahon C, Gore SD, Platanias LC, Levine R, Melnick A, Wickrema
A, Greally JM, Verma A. Aberrant
epigenetic and genetic marks are seen in
myelodysplastic leukocytes and reveal
Dock4 as a candidate pathogenic gene on
chromosome 7q. J Biol Chem 286:2521123, 2011. PMC3137092
Zhou L, McMahon C, Bhagat T, Alencar
C, Yu Y, Fazzari M, Sohal D, Heuck C,
Gundabolu K, Ng C, Mo Y, Shen W,
Wickrema A, Kong G, Friedman E, Sokol
L, Mantzaris I, Pellagatti A, Boultwood J,
Platanias LC, Steidl U, Yan L, Yingling
JM, Lahn MM, List A, Bitzer M, Verma
A. Reduced SMAD7 leads to overactivation of TGF-beta signaling in MDS that
can be reversed by a specific inhibitor of
TGF-beta receptor I kinase. Cancer Res
71:955-63, 2011. PMC3032816
Keerthivasan G, Small S, Liu H, Wickrema
A, Crispino JD. Vesicle trafficking plays
a novel role in erythroblast enucleation.
Blood 116:3331-40, 2010. PMC2995360
ZHANG, YANMING, MD
* Locke FL, Artz A, Rich E, Zhang Y, van
Besien K, Stock W. Feasibility of clofarabine
cytoreduction before allogeneic transplant
conditioning for refractory AML. Bone
Marrow Transplant 45:1692-8, 2010.
* # Godley LA, Njiaju UO, Green M,
Weiner H, Lin S, Odenike O, Rich ES,
Artz A, Van Besien K, Daugherty CK,
Zhang Y, Le Beau MM, Stock W, Larson
RA. Treatment of therapy-related myeloid
neoplasms with high-dose cytarabine/
mitoxantrone followed by hematopoietic
stem cell transplant. Leuk Lymphoma
51:995-1006, 2010.
Kim YC, Jung YC, Chen J, Alhasan AH,
Kaewsaard P, Zhang Y, Ma S, Rosen
S, Wang SM. Evidences showing wide
presence of small genomic aberrations in
chronic lymphocytic leukemia. BMC Res
Notes 3:341, 2010. PMC3016268
ZIMMERMAN, TODD, MD
Lin RJ, Curran JJ, Zimmerman TM, Song
J, Niewold TB, Sweiss NJ. Lenalidomide
for the treatment of cryoglobulinemia and
undifferentiated spondyloarthropathy in
a patient with multiple myeloma. J Clin
Rheumatol 16:90-1, 2010.
* # Poire X, Kline J, Grinblatt D, Zimmerman T, Conner K, Muhs C, Gajewski T,
Van Besien K, Smith SM. Phase II study
of immunomodulation with granulocytemacrophage colony-stimulating factor,
interleukin-2, and rituximab following
autologous stem cell transplant in patients
with relapsed or refractory lymphomas.
Leuk Lymphoma 51:1241-50, 2010.
Jakubowiak AJ, Griffith KA, Reece DE,
Hofmeister CC, Lonial S, Zimmerman
TM, Campagnaro EL, Schlossman
RL, Laubach JP, Raje NS, Anderson T,
Mietzel MA, Harvey CK, Wear SM, Barrickman JC, Tendler CL, Esseltine DL,
Kelley SL, Kaminski MS, Anderson KC,
Richardson PG. Lenalidomide, bortezomib, pegylated liposomal doxorubicin,
and dexamethasone in newly diagnosed
multiple myeloma: a phase 1/2 Multiple
Myeloma Research Consortium trial.
Blood 118:535-43, 2011.
Somlo G, Lashkari A, Bellamy W, Zimmerman TM, Tuscano JM, O’Donnell
MR, Mohrbacher AF, Forman SJ, Frankel
P, Chen HX, Doroshow JH, Gandara DR.
Phase II randomized trial of bevacizumab
versus bevacizumab and thalidomide for
relapsed/refractory multiple myeloma: a
California Cancer Consortium trial. Br J
Haematol 154:533-5, 2011.
Chapman MA, Lawrence MS, Keats JJ,
Cibulskis K, Sougnez C, Schinzel AC,
Harview CL, Brunet JP, Ahmann GJ, Adli
M, Anderson KC, Ardlie KG, Auclair D,
Baker A, Bergsagel PL, Bernstein BE, Drier
Y, Fonseca R, Gabriel SB, Hofmeister CC,
Jagannath S, Jakubowiak AJ, Krishnan
A, Levy J, Liefeld T, Lonial S, Mahan S,
Mfuko B, Monti S, Perkins LM, Onofrio
R, Pugh TJ, Rajkumar SV, Ramos AH,
Siegel DS, Sivachenko A, Stewart AK,
Trudel S, Vij R, Voet D, Winckler W,
Zimmerman T, Carpten J, Trent J, Hahn
WC, Garraway LA, Meyerson M, Lander
ES, Getz G, Golub TR. Initial genome
sequencing and analysis of multiple
myeloma. Nature 471:467-72, 2011.
Selected Major Grants and Awards
INVESTIGATOR
TITLE
PROJECT
START DATE
END DATE
TOTAL
ANNUAL
COST
CLASS
FUNDING AGENCY
The role of miR-126 in core-binding
factor (CBF) acute myeloid leukemia
7/1/2011
6/30/2015
$180,000
N/A
American Cancer
Society
JOHN
CUNNINGHAM
The genomic basis of therapy-related
acute myelogenous leukemia
10/1/2010
9/30/2011
$100,000
N/A
Hyundai Hope on
Wheels
LUCY GODLEY
ON01910.Na administered as a 72-hour
continuous intravenous infusion
every other week in myelodysplastic
syndrome patients with excess blasts
relapsing after, or refractory to, or
intolerant to azacitidine or decitabine
4/28/2011
4/27/2013
$131,775
N/A
Onconova
Therapeutics, Inc.
FOTINI
GOUNARI
Signaling in thymic selection
9/20/2010
8/31/2011
$390,000
R01
National Institutes of
Health
MICHAEL
THIRMAN
A phase 1b/2 open label study to
evaluate the safety and efficacy of TRU
016 in combination with bendamustine
vs. bendamustine alone in patients with
relapsed chronic lymphocytic leukemia
2/10/2011
9/30/2012
$107,170
N/A
Emergent Product
Development
Seattle, LLC
UCCCC SCIENTIFIC REPORT 2010 – 2011
JIANJUN
CHEN
Hematopoiesis and Hematological Malignancies
The Hematopoiesis and Hematological Malignancies Program has a funding base of $9,539,829 in annual total costs
(current as of July 2011). This sum includes $2,785,376 in NCI funding and $1,545,311 in other NIH funding. Due
to space constraints, only selected new awards since January 1, 2010 of $100,000 or greater in annual total costs are
listed here.
49
IMMUNOLOGY AND CANCER
PROGRAM LEADER
Thomas Gajewski,
MD, PhD
Professor of Pathology
and Medicine
50
HE IMMUNOLOGY AND CANCER PROGRAM AIMS TO
understand the interface between the host immune system and
malignant tumors. The Program, consisting of 22 members (one
of whom is a Howard Hughes investigator) from six departments,
deciphers all aspects of immune response against tumors to
develop immune-based cancer therapeutics. Program members
Immunology and Cancer
T
are bringing new immunology concepts into preclinical models
of anti-tumor immunity, translating fundamental discoveries into
clinical applications, and testing new hypotheses generated from
these studies back in murine models.
в– в– Fundamental investigations in immunology relevant
to cancer;
в– в– Studies using mouse models of anti-tumor immunity; and
в– в– Clinical studies of human anti-tumor immunity and
novel immunotherapies
UCCCC SCIENTIFIC REPORT 2010 – 2011
T H E OV E R A L L G OA L S O F T H E P R O G R A M A R E TO CO N D U C T:
51
UCCCC SCIENTIFIC REPORT 2010 – 2011 Immunology and Cancer
PROGRAM MEMBERSHIP†Erin Adams, PhD
Assistant Professor of Biochemistry
& Molecular Biology
Maria-Luisa Alegre, MD, PhD
Associate Professor of Medicine
Hans Schreiber, MD, PhD
Professor of Pathology
Anne Sperling, PhD
Associate Professor of Medicine
Albert Bendelac, MD, PhD
Professor of Pathology
Ursula Storb, MD
Professor of Molecular Genetics
& Cell Biology
Anita Chong, PhD
Professor of Surgery
Patrick Wilson, PhD, MS
Assistant Professor of Medicine
Marcus Clark, MD
Professor of Medicine
Ping Yu, MD
Assistant Professor of Pathology
Yang-Xin Fu, MD, PhD
Professor of Pathology
Jian Zhang, MD
Assistant Professor of Medicine
Thomas Gajewski, MD, PhD
Professor of Pathology and
Medicine
Tatyana Golovkina, PhD
Associate Professor of Microbiology
П†Jose Guevara-Patino, MD, PhD
Assistant Professor of Surgery
Bana Jabri, MD, PhD
Professor of Medicine
Justin Kline, MD
Assistant Professor of Medicine
Vinay Kumar, MD, PhD
Professor of Pathology
Maciej Lesniak, MD
Professor of Surgery
Vu Nguyen, MD
Assistant Professor of Medicine
Glenn Randall, PhD
Assistant Professor of Microbiology
Peter Savage, PhD
Assistant Professor of Pathology
†Reflects all Program membership during 2010-2011 
П† Individuals who are no longer at the UCCCC
52
Program Highlights††Due to space constraints, only a small representative sample of Program highlights is presented here.
SAP PROTEIN-DEPENDENT
NATURAL KILLER T-LIKE
CELLS REGULATE CD8+
T CELL DEVELOPMENT
(INTERPROGRAMMATIC)
abrogate antibody-initiated immunity
and decrease resistance to relapse.
These findings bear significant clinical
impact because they demonstrate that
anti-HER2 efficacy depends on the
host immune system, but also that
antibody-initiated tumor regression
can be impaired by certain chemotherapy regimens. (Park et al., Cancer
Cell 18:160-70, 2010)
THERAPEUTIC EFFECT OF
ANTI-HER2/NEU ANTIBODY
DEPENDS ON INNATE AND
ADAPTIVE IMMUNITY
GENE SIGNATURE IN
MELANOMA IS ASSOCIATED
WITH CLINICAL BENEFIT
Yang-Xin Fu, MD, PhD, and colleagues examined the mechanisms
of tumor regression induced by
anti-HER2/neu antibody therapy in
syngeneic wild-type mice. They found
that the therapeutic effect of this
treatment is dependent on the activation of innate immunity and T cells.
Furthermore, an increased influx of
both innate and adaptive immune
cells into the tumor microenvironment was increased by subsequent
antibody-induced immunity, which
leads to enhanced tumor regression.
Surprisingly, the addition of chemotherapeutic drugs was found to
Thomas Gajewski, MD, PhD, and
colleagues examined the potential
mechanisms of response versus resistance to antitumor immunity through
gene expression profiling of melanoma
metastases in the context of peptidebased vaccines. They profiled fresh
tumor biopsies obtained from patients
prior to tumor antigen vaccination
and found that T-cell markers and
specific chemokines were associated
with clinical benefit from immunization against melanoma antigens.
These studies suggest that a subset of
melanoma patients have metastatic
tumors containing an inflammatory
infiltrate that may be useful as a
UCCCC SCIENTIFIC REPORT 2010 – 2011
Albert Bendelac, MD, PhD, and
Barbara Kee, PhD (Hematopoiesis and Hematological Malignancies
Program), along with colleagues
examined the requirement for ld3 in
T cell development by investigating
the phenotype and function of CD8
T cells in ld3-/- mice. They found that
during thymocyte development, ld3
prevents CD8+ T cells from adopting
an innate-like fate characterized by
expression of the Eomesodermin
transcription factor, expression of a
memory surface marker phenotype,
and dependence on the SAP signaling
pathway. Induction of the innate-like
phenotype was dependent on the
production of interleukin-4 from an
expanded population of NK T-like
cells. These observations increase our
understanding of how innate-like
CD8+ T cells develop and function.
(Verykokakis et al., Immunity
33:203-15, 2010)
the eradication of aggressive cancers,
and that CD4+ T cell cooperation
with CD8+ cells is required for T cell
activation and during the effector
phase in the tumor microenvironment. These results indicate a new
role for CD4+ cells and demonstrate
the potential of stromal targeting for
cancer immunotherapy. (Schietinger
et al., J Exp Med 207:2469, 2010)
Immunology and Cancer
Publications
BYSTANDER KILLING
OF CANCER REQUIRES
COOPERATION OF CD4+ AND
CD8+ T CELLS DURING THE
EFFECTOR PHASE
Hans Schreiber, MD, PhD, and
colleagues have tested the efficacy of
stromal targeting in a non-transgenic
T cell model. Using immunocompetent mice, they tested whether a
normal host without prior immunization could eliminate cancer
cells through stromal targeting
and examined the role of CD4+ T
cells alongside CD8+ T cells in this
process. They have found that T cell
targeting of tumor stroma results in
53
Immunology and Cancer
UCCCC SCIENTIFIC REPORT 2010 – 2011 predictive marker for clinical benefit
from immunotherapy approaches
and guide the development of new
therapeutic interventions to overcome
tumor resistance. (Gajewski et al.,
Cancer J 16:399-403, 2010)
GRANULOCYTE-MACROPHAGE
COLONY-STIMULATING
FACTOR, INTERLEUKIN-2,
AND RITUXIMAB IMPROVE
SURVIVAL IN PATIENTS
WITH LYMPHOMA (INTRA/
INTERPROGRAMMATIC)
Justin Kline, MD, Thomas Gajewski,
MD, PhD, and colleagues including
Drs. Zimmerman, Van Besien, and
Smith (Hematopoiesis and Hematological Malignancies Program)
performed a phase II study to determine if granulocyte-macrophage
colony-stimulating factor in combination with rituximab and IL-2
could eliminate persistent minimal
residual disease and improve eventfree survival in patients with relapsed
non-Hodgkin lymphoma or Hodgkin
lymphoma following autologous stem
cell transplant. The combination
therapy was found to be feasible with
encouraging event-free and overall
survival rates. Further investigation
will require a comparative arm to
determine if this combination is beneficial. (Poire et al., Leuk Lymphoma
51:1241-50, 2010)
INNATE IMMUNE SENSING
OF RETROVIRAL INFECTION
VIA TOLL-LIKE RECEPTOR 7
OCCURS UPON VIRAL ENTRY
Tatyana Golovkina, PhD, and colleagues investigated the sensing
mechanisms underlying retrovirusspecific immune response using mice
from retrovirus-resistant strains.
They found that the ability to enter
the host cell was sufficient to trigger
antivirus humoral immune response,
and that virus sensing is dependent
on an endosomal Toll-like receptor
54
7 (TLR7) mechanism independent
of type I interferons. These results
indicate that viral entry is critical for
inducing efficient adaptive immunity
and contribute to our understanding
of mechanisms involved in developing retroviral resistance. (Kane et al.,
Immunity 35:135-145, 2011)
Grants
CYCLIN D3 CONTRIBUTES TO
LYMPHOCYTE DEVELOPMENT
The development of B cells is regulated by cytokines and expression
of the pre-B cell antigen receptor
(pre-BCR) on lymphocyte precursors
destined to become B cells. Marcus
Clark, MD, was awarded an R01
grant from the National Institute of
General Medical Sciences to determine the mechanisms that direct
this process. In previous studies,
Dr. Clark determined that cyclin
D3 is required for clonal expansion
of pre-B cells. These studies will
facilitate an improved understanding
of the development of B cells, which
can be active participants in antitumor immune responses.
Immunology and Cancer
Maciej Lesniak, MD, has developed
a novel approach for the treatment of
malignant brain tumors using neural
stem cells (NSC) as carriers of an
oncolytic adenovirus that directly
targets glioma stem cells. Supported
by a U01 award from the National
Institutes of Health, Dr. Lesniak
is testing the efficacy and safety of
virotherapy for malignant glioma to
advance this approach and potentially help improve disease outcome.
CBL-B INFLUENCES
SUSCEPTIBILITY TO ASTHMA
AND AUTOIMMUNITY
Casitas-B-lineage lymphoma protein-b (Cbl-b), an E3 ubiquitin ligase,
plays a role in maintaining a balance
between immunity and tolerance.
Funded by a National Institutes
of Health R01 grant, Jian Zhang,
MD, is determining the mechanisms
by which Cbl-b contributes to
autoimmunity, specifically through
regulation of T helper 2 (Th2) cell
differentiation and regulatory T cell
development. An improved understanding of the mechanisms of Cbl-b
action may lead to the development
of novel therapeutic approaches
for autoimmune diseases, allergic
asthma, and cancer.
is dependent on type I IFN and
lymphotoxin beta receptor (LTОІR).
Through a National Cancer Institute
R01 award, Dr. Fu is further examining the mechanisms by which local
radiation stimulates immunity to
develop novel, combination modalities for treating cancer.
COMBINED RADIATION AND
IMMUNOTHERAPY INDUCE
TUMOR REGRESSION
Glenn Randall, PhD, was awarded an
R01 grant from the National Institute
of Allergy and Infectious Diseases to
investigate the role of various human
genes in hepatitis C virus (HCV)
infection. Dr. Randall is molecularly
characterizing membrane trafficking
pathways and the role of host genes in
HCV entry into cells. These studies
will shed light on stages of the viral life
cycle and identify key roles of human
genes that may affect the development
of liver disease, including cancer, in
the HCV-infected population.
Established tumors exhibit barriers
that limit the eradication of metastases by immune destruction. Yang-Xin
Fu, MD, has shown that a large
single dose of radiotherapy (RT)
targeted against primary tumors can
destroy these barriers by increasing
cytotoxic T-lymphocyte (CTL)
cross-priming and antigen presentation. Furthermore, he demonstrated
that RT-induced tumor regression
UCCCC SCIENTIFIC REPORT 2010 – 2011
NEURAL STEM CELLS ARE
EFFECTIVE CARRIERS
OF VIROTHERAPY FOR
MALIGNANT GLIOMA
HOST GENES INFLUENCE
HEPATITIS C VIRUS
TRAFFICKING
55
Featured Faculty Profiles††Due to space constraints, only a small representative sample of Program members is presented here. UCCCC SCIENTIFIC REPORT 2010 – 2011 Immunology and Cancer
PATRICK WILSON, PHD, MS
Assistant Professor of Medicine
Dr. Patrick Wilson’s laboratory is interested in understanding the mechanisms
that mediate B cell responses and antibody-mediated immunity to infectious
diseases. Dr. Wilson also has a long-standing interest in the control of autoreactive B cells in immune tolerance. Over the years, his laboratory has developed
technologies to clone recombinant monoclonal antibodies from discrete populations of B cells. A major focus of the laboratory is using these approaches to
isolate antibodies that are protective against infectious agents such as influenza
and staphylococci. These antibodies will help identify targets for the rational
design of improved vaccines. Furthermore, his laboratory is developing the
antibodies themselves as the next class of drugs to treat these infections.
Dr. Wilson and his colleagues found that after influenza vaccination, a rapid
and robust influenza-specific IgG1 antibody-secreting plasmablast response
occurred.1 The response peaked at approximately day 7 and accounted for up
to 6% of peripheral blood B cells. By isolating single cells, they demonstrated
Patrick Wilson, PhD, MS
that numerous high-affinity antibodies could be isolated from humans within
a month after vaccination. This technology is now being used worldwide to
understand current, ongoing B cell responses during infections or after vaccination. New insights
on B cell responses will facilitate the development of novel therapeutics to treat or provide prophylactics against various infectious diseases, and will help identify the targets of human antibodies
and appropriate pathogens to target by vaccination. Dr. Wilson’s laboratory used this approach to
demonstrate a predominant memory cell origin of the influenza vaccine-induced response but with
rapid adaptation to novel vaccines. In a follow-up report, they demonstrated that the approach was
widely applicable and could be used after various vaccinations in addition to influenza, such as
Pneumovax, anthrax, and hepatitis B.2
Unlike antibodies elicited by annual influenza vaccinations, Dr. Wilson observed that most neutralizing antibodies induced by pandemic H1N1 infection were derived from activated memory B
cells specific for epitopes conserved in many influenza strains.3 Consequently, most neutralizing
antibodies were broadly reactive against divergent H1N1 and H5N1 influenza strains. This study
provides evidence that, given the right immunogen, a pan-influenza vaccine and the potential to
eradicate influenza as a human disease may be possible. The antibodies generated offered potent
protection and rescued mice from lethal challenge with pandemic H1N1 or antigenically distinct
influenza strains, making them excellent therapeutic candidates. Dr. Wilson hopes to apply a
similar technology toward the understanding of B cell responses against cancers.
Wrammert J, Smith K, Miller J, Langley WA, Kokko K, Larsen C, Zheng NY, Mays I, Garman L, Helms C, James J, Air GM,
Capra JD, Ahmed R, Wilson PC. Rapid cloning of high-affinity human monoclonal antibodies against influenza virus. Nature
453:667-671, 2008.
1
Smith K, Garman L, Wrammert J, Zheng NY, Capra JD, Ahmed R, Wilson PC. Rapid generation of fully human monoclonal
antibodies specific to a vaccinating antigen. Nat Protoc 4:372-384, 2008.
2
Wrammert J, Koutsonanos D, Li GM, Edupuganti S, Sui J, Morrissey M, McCausland M, Skountzou I, Hornig M, Lipkin WI,
Mehta A, Razavi B, Del Rio C, Zheng NY, Lee JH, Huang M, Ali Z, Kaur K, Andrews S, Amara RR, Wang Y, Das SR, O’Donnell
CD, Yewdell JW, Subbarao K, Marasco WA, Mulligan MJ, Compans R, Ahmed R, Wilson PC. Broadly cross-reactive antibodies
3
dominate the human B cell response against 2009 pandemic H1N1 influenza virus infection. J Exp Med 208:181-193, 2011.
56
Associate Professor of Medicine
Drs. Maria-Luisa Alegre and Anita Chong (Immunology and Cancer Program)
have been collaborating for the past 6 years, focusing on the consequences of
infections, and the immune signals that they elicit, on immune responses to
non-microbial antigens. This focus is relevant for cancer research, as observations of cancer regression in patients experiencing bacterial infections served
as some of the first historic reports suggesting a role of the immune system in
tumor elimination.
More recently, the Alegre and Chong laboratories have reported that LM, but not SA or CpG,
could abrogate transplantation tolerance when infection occurred months after cardiac allograft
acceptance.3 Rejection was recapitulated with a combination of recombinant IFNОІ plus IL-6,
demonstrating that reactivation of antigen-specific immune responses is more difficult after
animals achieve long-term tolerance. This model is more reminiscent of clinical settings of established cancer, in which tumor-specific T cells may be inactivated or suppressed. Understanding
the signals that can restore immune responses in this context may help find avenues to reestablish
anti-tumor immunity. A program project to continue these studies, aimed at dissecting pathways
that lead to robust and stable antigen-specific tolerance and the mechanisms by which stable tolerance can be abrogated, was recently submitted to the NIH. The project was favorably reviewed
and is awaiting council decision.
UCCCC SCIENTIFIC REPORT 2010 – 2011
The Alegre and Chong laboratories use mouse models of skin and heart
transplantation in which long-term tolerance of fully mismatched allografts
is induced by treatment with antibodies to the costimulatory molecule
CD154 (CD40L). The team has previously reported that ligation of Tolllike receptor 9 (TLR9), a receptor for unmethylated CpG motifs present in
bacteria, prevents the induction of transplantation tolerance, correlating with
reduced accumulation of regulatory T cells in the graft. Graft rejection was
Maria-Luisa Alegre, MD, PhD
dependent on IL-6/IL-17 in CpG-treated animals, suggesting that innate
cytokines can shape the differentiation phenotype of graft-reactive T cells.
Systemic bacterial infections with Listeria monocytogenes (LM) or Staphylococcus aureus (SA)
also prevented anti-CD154-mediated acceptance of skin allografts,1 whereas maximally tolerated
titers of Pseudomonas aeruginosa (PA) did not. LM infections prevented graft acceptance through
type I Interferon signaling while SA did so in an IL-6-dependent manner. Interestingly, steroid
administration reduced IL-6 production in SA-infected mice and prevented graft rejection. These
data demonstrate that distinct innate immune signals elicited by different bacteria variously affect
the immune response to transplant antigens and point to therapeutic targets to facilitate tolerance
induction in transplantation and autoimmunity.2
Immunology and Cancer
MARIA-LUISA ALEGRE, MD, PHD
Ahmed EB, Wang T, Daniels M, Alegre ML, Chong AS. IL-6 induced by Staphylococcus aureus infection prevents the induction of
skin allograft acceptance in mice. Am J Transplant 11:936-946, 2011.
1
Ahmed EB, Daniels M, Alegre ML, Chong AS. Bacterial infections, alloimmunity, and transplantation tolerance. Transplant Rev
25:27-35, 2011.
2
Wang T, Ahmed EB, Chen L, Xu J, Tao J, Wang CR, Alegre ML, Chong AS. Infection with the intracellular bacterium, Listeria
monocytogenes, overrides established tolerance in a mouse cardiac allograft model. Am J Transplant 10:1524-1533, 2010. 3
57
UCCCC SCIENTIFIC REPORT 2010 – 2011 Immunology and Cancer
YANG-XIN FU, MD, PHD
Professor of Pathology
Dr. Yang-Xin Fu is a physician scientist with a strong interest in basic immunobiology and tumor immunology. His studies often integrate basic research
with disease pathogenesis and treatment. Basic research in Dr. Fu’s laboratory
is focused on understanding the biological consequences arising from the
interaction between core molecules of the TNF superfamily, lymphotoxin (LT
or TNFSF1) and LIGHT (TNFSF14), on lymphocytes and their receptor,
LTОІR, on stromal cells. This research has contributed substantially to
defining the critical role of these molecules in the development and function
of primary, secondary, and tertiary lymphoid tissues. The overall goal of Dr.
Fu’s laboratory is to understand the role of innate and adaptive immunity in
conventional and targeted therapies and to develop new, targeted strategies
against local tumor tissues while generating systemic immune responses.
An understanding of the role of LIGHT and LT on the LTОІR-mediated
lymphoid microenvironment has allowed Dr. Fu to pioneer new approaches
Yang-Xin Fu, MD, PhD
for altering the lymphoid-like microenvironment to enhance infectious or
tumor immunity.1 Similarly, Dr. Fu will explore how to target tumors with
antibody-based fusion proteins to favor strong immunity.
Local radiotherapy (RT) can induce severe DNA damage, causing tumor dormancy. Dr. Fu’s
laboratory has revealed an essential role of CD8+ cells in suppressing tumor cell growth and
maintaining dormancy.2,3 They have identified an active interaction between tumor and immune
cells that is essential for dormancy, opening new avenues for the elimination of dormant cells. His
laboratory is further exploring how RT induces danger signals and cytokines to break tolerance.
Dr. Fu has also examined the influence of both innate and adaptive immunity in antibody-mediated
tumor regression. Current models propose that the therapeutic effect of HER2/neu antibody (Ab)
on HER2/neu+ breast cancer is mediated through the interruption of oncogenic signaling on tumor
cells and/or the induction of antibody-dependent, cell-mediated cytotoxicity (ADCC). However,
relapse often occurs after prolonged treatment. Unexpectedly, Dr. Fu’s laboratory has recently
demonstrated that the therapeutic effect of anti-neu Ab is largely dependent on HMGB-1, MyD88,
IFN-О±/ОІ, and CD8+, and CD4+ T cells.4 They are exploring how innate and adaptive cells interact
and developing methods to amplify antibody-mediated immunity. Together, this work demonstrates how the host immune response is critical to the efficacy of traditional cancer therapeutics.
Wang Y, Koroleva EP, Kruglov AA, Kuprash DV, Nedospasov SA, Fu YX, Tumanov AV. Lymphotoxin beta receptor signaling in
intestinal epithelial cells orchestrates innate immune responses against mucosal bacterial infection. Immunity 32:403-413, 2010.
1
2 Lee Y, Auh SL, Wang Y, Burnette B, Wang Y, Meng Y, Beckett M, Sharma R, Chin R, Tu T, Weichselbaum RR, Fu YX. Therapeutic
effects of ablative radiation on local tumor require CD8+ T cells: changing strategies for cancer treatment. Blood 114:589-595, 2010.
Burnette BC, Liang H, Lee Y, Chlewicki L, Khodarev NN, Weichselbaum RR, Fu YX, Auh SL. The efficacy of radiotherapy relies
upon induction of type i interferon-dependent innate and adaptive immunity. Cancer Res 71:2488-2496, 2011.
3
Park S, Jiang Z, Mortenson ED, Deng L, Radkevich-Brown O, Yang X, Sattar H, Wang Y, Brown NK, Greene M, Liu Y, Tang
J, Wang S, Fu YX. The therapeutic effect of anti-HER2/neu antibody depends on both innate and adaptive immunity. Cancer Cell
4
18:160-170, 2010.
58
Associate Professor of Microbiology
A proper host defense against viral pathogens exists at two levels: the innate
immunity response, and adaptive immunity resulting in long-lasting protective immunity. As with all infectious processes, susceptibility to retroviral
pathogenesis and tumorigenesis are both controlled by the genetic background of the host. Dr. Tatyana Golovkina is using Mouse Mammary Tumor
Virus (MMTV) as well as Murine Leukemia Virus (MuLV) to study different aspects of retrovirus-host interactions, including the anti-virus immune
response and the genetics of resistance to retroviral infection and to virally
induced tumors. Elucidation of the mechanism of retroviral pathogenesis is
of fundamental importance, as it will ultimately lead to increased knowledge
about the anti-virus immune response in general and variations in susceptibility to tumor-causing viruses in humans.
Mice from non-resistant strains are susceptible to various retroviruses even though they are capable
of sensing them. This is due to numerous mechanisms that retroviruses have evolved to counteract immune defenses. Many retroviruses, including MMTV, are transmitted most efficiently
through mucosal surfaces rich in microbiota. Dr. Golovkina’s laboratory found that MMTV,
when ingested by newborn mice, stimulates a state of unresponsiveness towards viral antigens.4
This process required the intestinal microbiota, as antibiotic-treated mice or germ-free mice did
not transmit infectious virus to their offspring. MMTV-bound bacterial lipopolysaccharide triggered Toll-like receptor 4 and subsequent interleukin (IL)-6-dependent induction of the inhibitory
cytokine IL-10. Thus, MMTV has evolved to rely on the interaction with the microbiota to induce
an immune evasion pathway. Together, these findings reveal the fundamental importance of commensal microbiota in viral infections.
UCCCC SCIENTIFIC REPORT 2010 – 2011
By using mice from two inbred strains that control retroviruses via adaptive
immune mechanisms and do not develop tumors,1,2 Dr. Golovkina’s laboraTatyana Golovkina, PhD
tory found that of all steps in viral replication, the ability to enter the host cell
was sufficient to induce anti-virus humoral immune responses.3 Virus sensing
occurred in endosomes via a MyD88-Toll-like receptor 7-dependent mechanism and stimulated
virus-neutralizing immunity independently of type I interferons. Thus, efficient adaptive immunity
to retroviruses is induced in vivo by innate sensing of the early stages of retroviral infection.
Immunology and Cancer
TATYANA GOLOVKINA, PHD
Case LK, Purdy A, Golovkina TV. Molecular and cellular basis of the retrovirus resistance in I/LnJ mice. J Immunol
175:7543-7549, 2005.
1
2
Kane M, Case LK, Golovkina TV. Vital role for CD8+ cells in controlling retroviral infections. J Virol 85:3415-23, 2011.
Kane M, Case LK, Wang C, Yurkovetskiy L, Dikiy S, Golovkina TV. Innate immune sensing of retroviral infection via toll-like
receptor 7 occurs upon viral entry. Immunity 35:135-145, 2011.
3
Kane M, Case LK, Kopaskie K, Kozlova A, MacDearmid C, Chervonsky A, and Golovkina TV. Successful transmission of a
retrovirus depends on the commensal microbiota. Science 334:245-249, 2011.
4
59
UCCCC SCIENTIFIC REPORT 2010 – 2011 Immunology and Cancer
BANA JABRI, MD, PHD
Professor of Medicine
Dr. Bana Jabri’s laboratory is identifying molecular targets that can be exploited
to promote or block inflammatory immune responses for the treatment of
cancer. Understanding how to modulate inflammatory immune responses
in tissues has two implications for cancer therapy: 1) to induce effective T
cell immunity against aseptic tolerogenic tissues to allow for the rejection
of established cancers; and 2) to avert unwanted, chronic response associated with the development of cancers, as seen in the context of inflammatory
bowel disease and celiac disease. Dr. Jabri’s work centers on understanding
the innate immune mechanisms that lead to activation of T cells in tissues.1,2
Specifically, she has studied the role of natural killer receptors and IL-15 in T
cell-mediated tissue immunity.
Dr. Jabri’s laboratory discovered that IL-15 licenses cytotoxic T cells to
become potent killer cells and acquire lymphokine killer properties.3 Intriguingly, reports have shown that NKG2D, when engaged in the absence of
Bana Jabri, MD, PhD
IL-15, is down-regulated and can no longer mediate its anti-tumor effects.
Recently, Dr. Jabri has reported in collaboration with her colleagues that
NKG2D engagement in the absence of inflammation promotes degradation of the T cell receptor,
hence inactivating T cells.4 Dr. Jabri’s laboratory is currently exploring indications that IL-15 may
counter these immunosuppressive effects. Furthermore, in collaboration with Dr. Hans Schreiber
(Immunology and Cancer Program), she found that IL-15 expression by tumor cells allows rejection of established solid tumors that express low levels of or even lack cognate antigen by cytotoxic
T cells (manuscript under review).
In addition to enhancing the innate and specific cytolytic properties of T cells, IL-15 can synergize
with the vitamin A metabolite, retinoic acid, to activate dendritic cells and promote inflammatory
helper type-1 and type-17 responses.5 This provides an explanation for how retinoic acid may have
adjuvant effects in cancer therapy, particularly when IL-15 can be induced. Conversely, Dr. Jabri
and colleagues are testing molecules that block IL-15 signaling for the treatment of pre-lymphoma in
patients with celiac disease.5 Finally, her laboratory is identifying molecules that promote the secretion
of IL-10 to prevent chronic inflammation associated with the development of intestinal cancers.6,7
1
Jabri B, Sollid LM. Tissue-mediated control of immunopathology in celiac disease. Nat Rev Immunol 9:858-870, 2009.
Abadie V, Sollid LM, Barreiro LB, Jabri B. Integration of genetic and immunological insights into a model of celiac disease pathogenesis. Annu Rev Immunol 29:493-525, 2011.
2
3 Tang F, Chen Z, Ciszewski C, Setty M, Solus J, Tretiakova M, Ebert E, Han J, Lin A, Guandalini S, Groh V, Spies T, Green P, Jabri B.
Cytosolic PLA2 is required for CTL-mediated immunopathology of celiac disease via NKG2D and IL-15. J Exp Med 206:707-719, 2009.
4 Hanaoka
N, Jabri B, Dai Z, Ciszewski C, Stevens AM, Yee C, Nakakuma H, Spies T, Groh V. NKG2D initiates caspase-mediated
CD3zeta degradation and lymphocyte receptor impairments associated with human cancer and autoimmune disease. J Immunol
185:5732-5742, 2010.
DePaolo RW, Abadie V, Tang F, Fehlner-Peach H, Hall JA, Wang W, Marietta EV, Kasarda DD, Waldmann TA, Murray JA,
Semrad C, Kupfer SS, Belkaid Y, Guandalini S, Jabri B. Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory
immunity to dietary antigens. Nature 471:220-224, 2011.
5
6 Depaolo RW, Tang F, Kim I, Han M, Levin N, Ciletti N, Lin A, Anderson D, Schneewind O, Jabri B. Toll-like receptor 6 drives dif-
ferentiation of tolerogenic dendritic cells and contributes to LcrV-mediated plague pathogenesis. Cell Host Microbe 4:350-361, 2008.
7 Round
JL, Lee SM, Li J, Tran G, Jabri B, Chatila TA, Mazmanian SK. The Toll-like receptor 2 pathway establishes colonization by
a commensal of the human microbiota. Science 332:974-977, 2011.
60
Immunology and Cancer
HANS SCHREIBER, MD, PHD
Professor of Pathology
Dr. Schreiber has a long-standing interesting in understanding the nature of
the host immune response against cancers. His laboratory was among the first
to identify the molecular nature of tumor antigens,1 and he has uncovered
a critical role for the tumor stroma in both supporting tumor growth and
facilitating tumor resistance to immune destruction.2 Most recently, he has
focused on the rules that govern whether adoptively transferred T cells can
eliminate established cancers and lead to cure in preclinical models.
While most of Dr. Schreiber’s work has focused upon anti-tumor CD8+ T
cells, he recently confirmed a therapeutic role for CD4+ T cells in tumor
control. Contrary to expectations, CD4+ T cells were not acting only during
the priming phase to provide T cell “help,” but rather during the effector
phase within the tumor microenvironment. These CD4+ T cells were facilitating destruction of tumor stroma, providing additional support for the notion
that destruction of stromal cells is a key component in cancer therapy.3
Hans Schreiber, MD, PhD
A key role for cytokines also has been observed with respect to the therapeutic effect of T cells on
controlling tumor growth when only the stroma is targeted. Dr. Schreiber’s group has discovered
that the cytokines IFN-Оі and TNF-О± are essential for the ability of T cells to promote bystander
control of solid tumors in vivo. This mechanism argues for the generation of polyfunctional T cells
producing inflammatory cytokines to maximize immune-mediated tumor control.5
Brooks CL, Schietinger A, Borisova SN, Kufer P, Okon M, Hirama T, Mackenzie CR, Wang LX, Schreiber H, Evans SV. Antibody
recognition of a unique tumor-specific glycopeptide antigen. PNAS 107:10056-10061, 2010.
1
UCCCC SCIENTIFIC REPORT 2010 – 2011
Because many tumors can acquire resistance to immune-mediated attack, Dr.
Schreiber’s group has recently studied the evolution of resistance over time using a mouse tumor
model. His group found that serial passage of a tumor in vivo was associated with loss of susceptibility to the growth-inhibitory effect of IFN-Оі. The lack of protective immunity occurred despite
retention of tumor antigens, arguing that IFN-Оі responsiveness of the tumor cells represents a
critical parameter that determines effectiveness of anti-tumor immunity.4
Zhang B, Zhang Y, Bowerman NA, Schietinger A, Fu YX, Kranz DM, Rowley DA, Schreiber H. Equilibrium between host and
cancer caused by effector T cells killing tumor stroma. Cancer Res 68:1563-1571, 2008.
2
Schietinger A, Philip M, Liu RB, Schreiber K, Schreiber H. Bystander killing of cancer requires the cooperation of CD4(+) and
CD8(+) T cells during the effector phase. J Exp Med 207:2469-2477, 2010.
3
4 Wu TH, Schreiber K, Arina A, Khodarev NN, Efimova EV, Rowley DA, Weichselbaum RR, Schreiber H. Progression of cancer
from indolent to aggressive despite antigen retention and increased expression of interferon-gamma inducible genes. Cancer Immun
11:2, 2011.
Zhang B, Karrison T, Rowley DA, Schreiber H. IFN-gamma- and TNF-dependent bystander eradication of antigen-loss variants
in established mouse cancers. J Clin Invest 118:1398-1404, 2008.
5
61
Selected Publications
UCCCC SCIENTIFIC REPORT 2010 – 2011 Immunology and Cancer
* : Intraprogrammatic Collaboration
# : Interprogrammatic Collaboration
ADAMS, ERIN, PHD
Kazen AR, Adams EJ. Evolution of the V,
D, and J gene segments used in the primate
gammadelta T-cell receptor reveals a
dichotomy of conservation and diversity.
PNAS 108:E332-40, 2011. PMC3141992
Scharf L, Li NS, Hawk AJ, Garzon D,
Zhang T, Fox LM, Kazen AR, Shah S,
Haddadian EJ, Gumperz JE, Saghatelian
A, Faraldo-Gomez JD, Meredith SC, Piccirilli JA, Adams EJ. The 2.5 a structure
of CD1c in complex with a mycobacterial
lipid reveals an open groove ideally suited
for diverse antigen presentation. Immunity
33:853-62, 2010. PMC3010391
Older Aguilar AM, Guethlein LA, Adams
EJ, Abi-Rached L, Moesta AK, Parham P.
Coevolution of killer cell Ig-like receptors
with HLA-C to become the major variable
regulators of human NK cells. J Immunol
185:4238-51, 2010. PMC3124317
# Lodolce JP, Kolodziej LE, Rhee L,
Kariuki SN, Franek BS, McGreal NM,
Logsdon MF, Bartulis SJ, Perera MA,
Ellis NA, Adams EJ, Hanauer SB, Jolly M,
Niewold TB, Boone DL. African-derived
genetic polymorphisms in TNFAIP3
mediate risk for autoimmunity. J Immunol
184:7001-9, 2010.
* # Verykokakis M, Boos MD, Bendelac
A, Adams EJ, Pereira P, Kee BL. Inhibitor
of DNA binding 3 limits development of
murine slam-associated adaptor proteindependent “innate” gammadelta T cells.
PLoS One 5:e9303, 2010. PMC2824806
ALEGRE, MARIA-LUISA, MD, PHD
* Wang T, Ahmed EB, Chen L, Xu J,
Tao J, Wang CR, Alegre ML, Chong AS.
Infection with the intracellular bacterium, Listeria monocytogenes, overrides
established tolerance in a mouse cardiac
allograft model. Am J Transplant 10:152433, 2010.
* Bhorade SM, Chen H, Molinero
L, Liao C, Garrity ER, Vigneswaran
WT, Shilling R, Sperling A, Chong A,
Alegre ML. Decreased percentage of
CD4+FoxP3+ cells in bronchoalveolar
lavage from lung transplant recipients correlates with development of bronchiolitis
obliterans syndrome. Transplantation
90:540-6, 2010.
62
Sweiss NJ, Salloum R, Gandhi S, Alegre
ML, Sawaqed R, Badaracco M, Pursell
K, Pitrak D, Baughman RP, Moller DR,
Garcia JG, Niewold TB. Significant CD4,
CD8, and CD19 lymphopenia in peripheral blood of sarcoidosis patients correlates
with severe disease manifestations. PLoS
One 5:e9088, 2010. PMC2816716
* Ahmed EB, Wang T, Daniels M, Alegre
ML, Chong AS. IL-6 induced by Staphylococcus aureus infection prevents the
induction of skin allograft acceptance in
mice. Am J Transplant 11:936-46, 2011.
PMC3083487
* Ahmed EB, Daniels M, Alegre ML,
Chong AS. Bacterial infections, alloimmunity, and transplantation tolerance.
Transplant Rev (Orlando) 25:27-35, 2011.
PMC2998288
Molinero LL, Miller ML, Evaristo C,
Alegre ML. High TCR stimuli prevent
induced regulatory T cell differentiation
in a NF-kappaB-dependent manner. J
Immunol 186:4609-17, 2011.
BENDELAC, ALBERT, MD, PHD
Constantinides MG, Picard D, Savage
AK, Bendelac A. A naive-like population
of human CD1d-restricted T cells expressing intermediate levels of promyelocytic
leukemia zinc finger. J Immunol 187:30915, 2011. PMC3119760
Thomas SY, Scanlon ST, Griewank KG,
Constantinides MG, Savage AK, Barr
KA, Meng F, Luster AD, Bendelac A.
PLZF induces an intravascular surveillance program mediated by long-lived
LFA-1-ICAM-1 interactions. J Exp Med
208:1179-88, 2011.
Savage AK, Constantinides MG, Bendelac
A. Promyelocytic leukemia zinc finger
turns on the effector T cell program
without requirement for agonist TCR
signaling. J Immunol 186:5801-6, 2011.
* # Verykokakis M, Boos MD, Bendelac
A, Adams EJ, Pereira P, Kee BL. Inhibitor
of DNA binding 3 limits development of
murine slam-associated adaptor proteindependent “innate” gammadelta T cells.
PLoS One 5:e9303, 2010. PMC2824806
# Verykokakis M, Boos MD, Bendelac A,
Kee BL. SAP protein-dependent natural
killer T-like cells regulate the development
of CD8(+) T cells with innate lymphocyte
characteristics. Immunity 33:203-15,
2010. PMC2933745
Wang L, Carr T, Xiong Y, Wildt KF, Zhu
J, Feigenbaum L, Bendelac A, Bosselut
R. The sequential activity of Gata3 and
Thpok is required for the differentiation of
CD1d-restricted CD4+ NKT cells. Eur J
Immunol 40:2385-90, 2010.
Freigang S, Zadorozhny V, McKinney
MK, Krebs P, Herro R, Pawlak J, Kain
L, Schrantz N, Masuda K, Liu Y, Savage
PB, Bendelac A, Cravatt BF, Teyton L.
Fatty acid amide hydrolase shapes NKT
cell responses by influencing the serum
transport of lipid antigen in mice. J Clin
Invest 120:1873-84, 2010. PMC2877940
CHONG, ANITA, PHD
* Ahmed EB, Wang T, Daniels M, Alegre
ML, Chong AS. IL-6 induced by Staphylococcus aureus infection prevents the
induction of skin allograft acceptance in
mice. Am J Transplant 11:936-46, 2011.
PMC3083487
Burns AM, Chong AS. Alloantibodies
prevent the induction of transplantation
tolerance by enhancing alloreactive T cell
priming. J Immunol 186:214-21, 2011.
* Ahmed EB, Daniels M, Alegre ML,
Chong AS. Bacterial infections, alloimmunity, and transplantation tolerance.
Transplant Rev (Orlando) 25:27-35, 2011.
PMC2998288
FU, YANG-XIN, MD, PHD
Park S, Jiang Z, Mortenson ED, Deng
L, Radkevich-Brown O, Yang X, Sattar
H, Wang Y, Brown NK, Greene M, Liu
Y, Tang J, Wang S, Fu YX. The therapeutic effect of anti-HER2/neu antibody
depends on both innate and adaptive
immunity. Cancer Cell 18:160-70, 2010.
PMC2923645
Washburn ML, Kovalev GI, Koroleva E,
Fu YX, Su L. LIGHT induces distinct
signals to clear an AAV-expressed persistent antigen in the mouse liver and to
induce liver inflammation. PLoS One
5:e10585, 2010. PMC2871052
# Burnette BC, Liang H, Lee Y, Chlewicki
L, Khodarev NN, Weichselbaum RR,
Fu YX, Auh SL. The efficacy of radiotherapy relies upon induction of type i
interferon-dependent innate and adaptive
immunity. Cancer Res 71:2488-96, 2011.
PMC3070872
* Wang Y, Zhu M, Yu P, Fu YX. Promoting immune responses by LIGHT in the
face of abundant regulatory T cell inhibition. J Immunol 184:1589-95, 2010.
* # Chen L, Park SM, Tumanov AV,
Hau A, Sawada K, Feig C, Turner JR, Fu
YX, Romero IL, Lengyel E, Peter ME.
CD95 promotes tumour growth. Nature
465:492-6, 2010. PMC2879093
Jang IK, Cronshaw DG, Xie LK, Fang
G, Zhang J, Oh H, Fu YX, Gu H,
Zou Y. Growth-factor receptor-bound
protein-2 (Grb2) signaling in B cells
controls lymphoid follicle organization
and germinal center reaction. PNAS
108:7926-31, 2011. PMC3093453
GAJEWSKI, THOMAS, MD, PHD
O’Day SJ, Maio M, Chiarion-Sileni
V, Gajewski TF, Pehamberger H,
Bondarenko IN, Queirolo P, Lundgren
L, Mikhailov S, Roman L, Verschraegen
C, Humphrey R, Ibrahim R, de Pril V,
Hoos A, Wolchok JD. Efficacy and safety
of ipilimumab monotherapy in patients
with pretreated advanced melanoma: a
multicenter single-arm phase II study.
Ann Oncol 21:1712-7, 2010.
Gajewski TF, Louahed J, Brichard VG.
Gene signature in melanoma associated
with clinical activity: a potential clue to
unlock cancer immunotherapy. Cancer J
16:399-403, 2010.
Gajewski TF. Improved melanoma
survival at last! Ipilimumab and a paradigm
tumor targeting. Cancer Immunol Immunother 59:851-62, 2010.
* # Poire X, Kline J, Grinblatt D, Zimmerman T, Conner K, Muhs C, Gajewski T,
Van Besien K, Smith SM. Phase II study
of immunomodulation with granulocytemacrophage colony-stimulating factor,
interleukin-2, and rituximab following
autologous stem cell transplant in patients
with relapsed or refractory lymphomas.
Leuk Lymphoma 51:1241-50, 2010.
# Bellavance EC, Kohlhapp FJ, Zloza A,
O’Sullivan JA, McCracken J, Jagoda MC,
Lacek AT, Posner MC, Guevara-Patino
JA. Development of tumor-infiltrating
CD8+ T cell memory precursor effector
cells and antimelanoma memory responses
are the result of vaccination and TGF-beta
blockade during the perioperative period
of tumor resection. J Immunol 186:330916, 2011. PMC3048906
* Gajewski TF, Fuertes M, Spaapen R,
Zheng Y, Kline J. Molecular profiling
to identify relevant immune resistance
mechanisms in the tumor microenvironment. Curr Opin Immunol 23:286-92,
2011. PMC3070788
* Kline J, Gajewski TF. Clinical development of mAbs to block the PD1 pathway
as an immunotherapy for cancer. Curr
Opin Investig Drugs 11:1354-9, 2010.
Locke F, Clark JI, Gajewski TF. A phase
II study of oxaliplatin, docetaxel, and
GM-CSF in patients with previously
treated advanced melanoma. Cancer Chemother Pharmacol 65:509-14, 2010.
# Driessens G, Zheng Y, Locke F, Cannon
JL, Gounari F, Gajewski TF. Beta-catenin
inhibits T cell activation by selective
interference with linker for activation of T
cells-phospholipase C-gamma1 phosphorylation. J Immunol 186:784-90, 2011.
GOLOVKINA, TATYANA, PHD
Kane M, Golovkina T. Common threads
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Kane M, Case LK, Golovkina TV. Vital
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PMC3067886
GUEVARA-PATINO, JOSE, MD, PHD
Norell H, Zhang Y, McCracken J, Martins
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PMC3050990
UCCCC SCIENTIFIC REPORT 2010 – 2011
Lasaro MO, Sazanovich M, Giles-Davis
W, Mrass P, Bunte RM, Sewell DA,
Hussain SF, Fu YX, Weninger W, Paterson
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Immunology and Cancer
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vaccination against human papillomavirus
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regression. Cancer Res 70:3955-64, 2010.
PMC2873073
JABRI, BANA, MD, PHD
# DePaolo RW, Abadie V, Tang F, FehlnerPeach H, Hall JA, Wang W, Marietta EV,
Kasarda DD, Waldmann TA, Murray JA,
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471:220-4, 2011. PMC3076739
Wang Y, Devkota S, Musch MW, Jabri B,
Nagler C, Antonopoulos DA, Chervonsky
63
Immunology and Cancer
A, Chang EB. Regional mucosa-associated
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Hanaoka N, Jabri B, Dai Z, Ciszewski C,
Stevens AM, Yee C, Nakakuma H, Spies
T, Groh V. NKG2D initiates caspasemediated CD3zeta degradation and
lymphocyte receptor impairments associated with human cancer and autoimmune
disease. J Immunol 185:5732-42, 2010.
PMC3044081
Round JL, Lee SM, Li J, Tran G, Jabri B,
Chatila TA, Mazmanian SK. The Toll-like
receptor 2 pathway establishes colonization
by a commensal of the human microbiota.
Science 332:974-7, 2011. PMC3164325
UCCCC SCIENTIFIC REPORT 2010 – 2011 Abadie V, Sollid LM, Barreiro LB, Jabri
B. Integration of genetic and immunological insights into a model of celiac disease
pathogenesis. Annu Rev Immunol 29:493525, 2011.
# Hu S, Wang Y, Lichtenstein L, Tao
Y, Musch MW, Jabri B, Antonopoulos
D, Claud EC, Chang EB. Regional differences in colonic mucosa-associated
microbiota determine the physiological
expression of host heat shock proteins.
Am J Physiol Gastrointest Liver Physiol
299:G1266-75, 2010. PMC3006241
Yoshida K, Corper AL, Herro R, Jabri B,
Wilson IA, Teyton L. The diabetogenic
mouse MHC class II molecule I-Ag7 is
endowed with a switch that modulates
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2010. PMC2860908
KLINE, JUSTIN, MD
* Kline J, Gajewski TF. Clinical development of mAbs to block the PD1 pathway
as an immunotherapy for cancer. Curr
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* Gajewski TF, Fuertes M, Spaapen R,
Zheng Y, Kline J. Molecular profiling
to identify relevant immune resistance
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2011. PMC3070788
* # Poire X, Kline J, Grinblatt D, Zimmerman T, Conner K, Muhs C, Gajewski T,
Van Besien K, Smith SM. Phase II study
of immunomodulation with granulocytemacrophage colony-stimulating factor,
interleukin-2, and rituximab following
autologous stem cell transplant in patients
with relapsed or refractory lymphomas.
Leuk Lymphoma 51:1241-50, 2010.
64
# Kenkre VP, Horowitz S, Artz AS, Liao
C, Cohen KS, Godley LA, Kline JP,
Smith SM, Stock W, van Besien K. T-celldepleted allogeneic transplant without
donor leukocyte infusions results in excellent long-term survival in patients with
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inhibit the growth of human xenograft
malignant glioma. PLoS One 5:e9750,
2010. PMC2841188
KUMAR, VINAY, MD, PHD
# Ferguson SD, Musleh W, Gurbuxani
S, Shafizadeh SF, Lesniak MS. Intracranial mucosa-associated lymphoid tissue
(MALT) lymphoma. J Clin Neurosci
17:666-9, 2010.
Chlewicki LK, Kumar V. A model system
for studying NK cell receptor signaling.
Methods Mol Biol 612:177-98, 2010.
Lian RH, Kumar V. Use of stem cell radiation chimeras to analyze how domains of
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Biol 612:51-65, 2010.
LESNIAK, MACIEJ, MD
Balyasnikova IV, Ferguson SD, Han Y,
Liu F, Lesniak MS. Therapeutic effect
of neural stem cells expressing TRAIL
and bortezomib in mice with glioma
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PMC3159776
Ahmed AU, Tyler MA, Thaci B, Alexiades NG, Han Y, Ulasov IV, Lesniak
MS. A comparatives study of neural and
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Ahmed AU, Thaci B, Alexiades NG, Han
Y, Qian S, Liu F, Balyasnikova IV, Ulasov
IY, Aboody KS, Lesniak MS. Neural stem
cell-based cell carriers enhance therapeutic
efficacy of an oncolytic adenovirus in an
orthotopic mouse model of human glioblastoma. Mol Ther 19:1714-26, 2011.
Ulasov IV, Nandi S, Dey M, Sonabend
AM, Lesniak MS. Inhibition of Sonic
hedgehog and Notch pathways enhances
sensitivity of CD133(+) glioma stem
cells to temozolomide therapy. Mol Med
17:103-12, 2011. PMC3022974
Ahmed AU, Rolle CE, Tyler MA, Han
Y, Sengupta S, Wainwright DA, Balyasnikova IV, Ulasov IV, Lesniak MS. Bone
marrow mesenchymal stem cells loaded
with an oncolytic adenovirus suppress the
anti-adenoviral immune response in the
cotton rat model. Mol Ther 18:1846-56,
2010. PMC2951553
Balyasnikova IV, Ferguson SD, Sengupta
S, Han Y, Lesniak MS. Mesenchymal
stem cells modified with a single-chain
Kim DH, Rozhkova EA, Ulasov IV, Bader
SD, Rajh T, Lesniak MS, Novosad V.
Biofunctionalized magnetic-vortex microdiscs for targeted cancer-cell destruction.
Nat Mater 9:165-71, 2010. PMC2810356
NGUYEN, VU, MD
Murphy S, Nguyen VH. Role of gut
microbiota in graft-versus-host disease.
Leuk Lymphoma, 2011.
Nguyen VH. Balancing act for Treg
immunotherapy. Blood 117:2751-2, 2011.
RANDALL, GLENN, PHD
Heaton NS, Perera R, Berger KL, Khadka
S, Lacount DJ, Kuhn RJ, Randall G.
Dengue virus nonstructural protein 3
redistributes fatty acid synthase to sites of
viral replication and increases cellular fatty
acid synthesis. PNAS 107:17345-50, 2010.
PMC2951450
Berger KL, Kelly SM, Jordan TX, Tartell
MA, Randall G. Hepatitis C virus stimulates the phosphatidylinositol 4-kinase
III alpha-dependent phosphatidylinositol
4-phosphate production that is essential
for its replication. J Virol 85:8870-83,
2011.
SAVAGE, PETER, PHD
Donkor MK, Sarkar A, Savage PA,
Franklin RA, Johnson LK, Jungbluth
AA, Allison JP, Li MO. T cell surveillance
of oncogene-induced prostate cancer is
impeded by T cell-derived TGF-beta1
cytokine. Immunity 35:123-34, 2011.
SCHREIBER, HANS, MD, PHD
# Schreiber H, Rowley JD, Rowley DA.
Targeting mutations predictably. Blood
118:830-1, 2011.
Schietinger A, Philip M, Liu RB, Schreiber K, Schreiber H. Bystander killing of
cancer requires the cooperation of CD4(+)
and CD8(+) T cells during the effector
phase. J Exp Med 207:2469-77, 2010.
PMC2964573
Brooks CL, Schietinger A, Borisova SN,
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CR, Wang LX, Schreiber H, Evans SV.
Antibody recognition of a unique tumorspecific glycopeptide antigen. PNAS
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Philip M, Schietinger A, Schreiber H.
Ribosomal versus non-ribosomal cellular
antigens: factors determining efficiency
of indirect presentation to CD4+ T
cells. Immunology 130:494-503, 2010.
PMC2913260
Aggen DH, Chervin AS, Schmitt TM,
Engels B, Stone JD, Richman SA, Piepenbrink KH, Baker BM, Greenberg PD,
Schreiber H, Kranz DM. Single-chain ValphaVbeta T-cell receptors function without
mispairing with endogenous TCR chains.
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cancer from indolent to aggressive despite
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SPERLING, ANNE, PHD
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# Cannon JL, Mody PD, Blaine KM,
Chen EJ, Nelson AD, Sayles LJ, Moore
TV, Clay BS, Dulin NO, Shilling RA,
Burkhardt JK, Sperling AI. CD43 interaction with ezrin-radixin-moesin (ERM)
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CD43 phosphorylation. Mol Biol Cell
22:954-63, 2011. PMC3069020
STORB, URSULA, MD
Ratnam S, Bozek G, Nicolae D, Storb
U. The pattern of somatic hypermutation
of Ig genes is altered when p53 is inactivated. Mol Immunol 47:2611-8, 2010.
PMC3038623
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* Wang Y, Zhu M, Yu P, Fu YX. Promoting immune responses by LIGHT in the
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Xu C, Feng D, Li L, Yu P, Hu X, Liu Y.
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UCCCC SCIENTIFIC REPORT 2010 – 2011
Schreiber HA, Prechl J, Jiang H, Zozulya
A, Fabry Z, Denes F, Sandor M. Using
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PMC2897891
ZHANG, JIAN, MD
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overexpressing cellular FLICE inhibitory protein in T cells causes lupus-like
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strain. Cell Death Differ 17:522-33, 2010.
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65
66
UCCCC SCIENTIFIC REPORT 2010 – 2011 Immunology and Cancer
Selected Major Grants and Awards
INVESTIGATOR
TITLE
PROJECT
START DATE
END DATE
TOTAL
ANNUAL
COST
CLASS
FUNDING AGENCY
Medical Scientist National Research
Service Award
7/1/2010
6/30/2013
$1,100,000
T32
National Institute
of General Medical
Sciences
MARCUS
CLARK
Regulation of cyclin D3 in B lymphocyte
development
9/1/2010
7/31/2014
$316,451
R01
National Institute
of General Medical
Sciences
YANG-XIN FU
Synergy of radiation and
immunotherapy: new approaches
7/1/2010
12/31/2014
$353,238
R01
National Cancer
Institute
YANG-XIN FU
TNF family members for lymph
angiogenesis and lymph node
hypertrophy
5/1/2010
2/28/2015
$313,989
R01
National Cancer
Institute
YANG-XIN FU
The role of negative signal in early
infection
6/1/2010
5/31/2012
$231,660
R21
National Institutes of
Health
THOMAS
GAJEWSKI
A phase I, open-label, dose-escalation
study to determine the safety,
tolerability, pharmacokinetics and
pharmacodynamics of INCB024360 in
patients with advanced malignancies
6/11/2010
6/10/2012
$260,500
N/A
Incyte
Pharmaceuticals, Inc.
BANA JABRI
IL-15, NK receptors and adaptive
immunity in celiac disease
9/1/2010
8/31/2015
$384,624
R01
National Institutes of
Health
MACIEJ
LESNIAK
Neural stem cell-based virotherapy for
malignant glioma
7/1/2010
6/30/2015
$1,238,138
U01
National Institute
of Neurological
Disorders and Stroke
VU NGUYEN
An open-label, multi-center, three
arm randomized, phase 3 study to
compare the efficacy and safety
of RO5072759 + GC1b, rituximab +
chlorambucil or chlorambucil alone in
previously untreated CLL patients with
comorbidities
10/7/2010
2/28/2012
$123,874
N/A
Hoffmann-Laroche
VU NGUYEN
Preserving tumor immunity following
hematopoietic stem cell transplantation
11/1/2010
10/31/2012
$100,000
N/A
The V Foundation
GLENN
RANDALL
Hepatitis C virus trafficking in infected
hepatocytes
5/1/2010
4/30/2015
$342,700
R01
National Institutes of
Health
GLENN
RANDALL
Membrane reorganization in hepatitis C
virus infection
1/1/2010
12/31/2013
$215,000
N/A
American Cancer
Society
JERROLD
TURNER
Mechanisms and consequences of
cytokine-induced tight junction barrier
regulation
7/15/2010
6/30/2014
$474,305
R01
National Institute of
Diabetes & Digestive
& Kidney Diseases
PATRICK
WILSON
Human monoclonal antibodies
5/1/2010
4/30/2011
$187,200
U19
National Institutes of
Health
JIAN ZHANG
Cb-I in T cell activation and
autoimmunity
7/1/2010
6/30/2014
$386,100
R01
National Institutes of
Health
UCCCC SCIENTIFIC REPORT 2010 – 2011
MARCUS
CLARK
Immunology and Cancer
The Immunology and Cancer Program has a funding base of $16,876,879 in annual total costs (current as of July 2011). This sum
includes $3,288,485 in NCI funding and $10,710,293 in other NIH funding. Due to space constraints, only selected new awards since
January 1, 2010 of $100,000 or greater in annual total costs are listed here.
67
PHARMACOGENOMICS AND
EXPERIMENTAL THERAPEUTICS
PROGRAM LEADERS
M. Eileen Dolan, PhD
Professor of Medicine
68
Walter Stadler, MD
Professor of Medicine
HE OVERALL GOAL OF THE PHARMACOGENOMICS AND
Experimental Therapeutics Program is to foster interaction
between basic and clinical investigators to develop innovative
therapies for cancer patients. Program members, consisting of
a diverse team of 54 investigators representing nine academic
departments, place an emphasis on translational and clinical
research as well as lead studies conducted by national clinical
trials cooperative groups. The Program participates in all phases
of clinical drug development, from preclinical to early phase to
cooperative group-led phase III trials, with a strong focus on
pharmacogenomics and pharmacology.
в– в– Pursue a broad program of preclinical, translational, and
clinical research in pharmacogenetics and pharmacology;
в– в– Foster interaction between basic and clinical investigators
that will result in innovative and effective therapies; and
UCCCC SCIENTIFIC REPORT 2010 – 2011
T H E S C I E N T I F I C A I M S O F T H E P R O G R A M A R E TO :
Pharmacogenomics and Experimental Therapeutics
T
в– в– Integrate new drugs into the development of multimodality
therapies for patients with advanced solid tumors.
69
UCCCC SCIENTIFIC REPORT 2010 – 2011
Pharmacogenomics and Experimental Therapeutics
PROGRAM MEMBERSHIP†Douglas Bishop, PhD
Professor of Radiation & Cellular
Oncology
Edwin Kaplan, MD
Professor of Surgery
П†Joseph Salama, MD
Assistant Professor of Radiation &
Cellular Oncology
Elizabeth Blair, MD
Associate Professor of Surgery
Theodore Karrison, PhD
Associate Professor of Health
Studies
Daniel Catennaci, MD
Instructor of Medicine
Hedy Kindler, MD
Associate Professor of Medicine
Tanguy Seiwert, MD
Assistant Professor of Medicine
Ezra Cohen, MD
Associate Professor of Medicine
Mark Lingen, DDS, PhD
Associate Professor of Pathology
Arieh Shalhav, MD
Professor of Surgery
Susan Cohn, MD
Professor of Pediatrics
Marcy List, PhD
Associate Director of Administration
UCCCC
П†Mark Siegler, MD
Professor of Medicine
Philip Connell, MD
Associate Professor of Radiation &
Cellular Oncology
П†Yves Lussier, MD
Associate Professor of Medicine
Christopher Daugherty, MD
Professor of Medicine
Michael Maitland, MD, PhD
Assistant Professor of Medicine
M. Eileen Dolan, PhD
Professor of Medicine
Bruce Minsky, MD
Professor of Radiation & Cellular
Oncology
Scott Eggener, MD
Assistant Professor of Surgery
Mark Ferguson, MD
Professor of Surgery
Alessandro Fichera, MD
Associate Professor of Surgery
Gini Fleming, MD
Professor of Medicine
Daniel Haraf, MD, MS
Professor of Radiation & Cellular
Oncology
Rita Nanda, MD
Assistant Professor of Medicine
M. Kelly Nicholas, MD, PhD
Assistant Professor of Neurology
Peter H. O’Donnell, MD
Instructor of Medicine
Terrance Peabody, MD
Professor of Surgery
Louis Portugal, MD
Associate Professor of Surgery
Richard Schilsky, MD
Professor of Medicine
David Song, MD, MBA
Professor of Surgery
Walter Stadler, MD
Professor of Medicine
Gary Steinberg, MD
Professor of Surgery
Kerstin Stenson, MD
Professor of Surgery
Russell Szmulewitz, MD
Assistant Professor of Medicine
Ronald Thisted, PhD
Professor of Health Studies
Victoria Villaflor, MD
Assistant Professor of Medicine
Everett Vokes, MD
Professor of Medicine
Ralph Weichselbaum, MD
Professor of Radiation & Cellular
Oncology
John Hart, MD
Professor of Pathology
П†Edwin Posadas, MD
Assistant Professor of Medicine
Chuan He, PhD
Professor of Chemistry
Mitchell Posner, MD
Professor of Surgery
Philip Hoffman, MD
Professor of Medicine
Mark Ratain, MD
Professor of Medicine
S. Diane Yamada, MD
Professor of Obstetrics &
Gynecology
R. Stephanie Huang, PhD
Assistant Professor of Medicine
Kevin Roggin, MD
Associate Professor of Surgery
Bakhtiar Yamini, MD
Assistant Professor of Surgery
П†Federico Innocenti, MD, PhD
Assistant Professor of Medicine
Charles Rubin, MD
Associate Professor of Pediatrics
Chun-Su Yuan, MD, PhD
Associate Professor of Anesthesia/
Critical Care
H. Rosie Xing, PhD
Assistant Professor of Pathology
†  Reflects all Program membership during 2010-2011 
φ  Individuals who are no longer at the UCCCC
70
Program Highlights††Due to space constraints, only a small representative sample of Program highlights is presented here.
SNPS ASSOCIATED WITH
CHEMOTHERAPEUTIC DRUG
SUSCEPTIBILITY ARE ENRICHED
IN EXPRESSION QUANTITATIVE
TRAIT LOCI (INTRA/
INTERPROGRAMMATIC)
GEFITINIB AND
CHEMORADIOTHERAPY
CONTROL LOCALLY
ADVANCED HEAD AND
NECK CANCER (INTRA/
INTERPROGRAMMATIC)
Everett Vokes, MD, and Ezra Cohen,
MD, assessed the efficacy and toxicity
of gefitinib in locally advanced head
and neck cancer (LA-HNC). Collaborators in this study included
Drs. Haraf, Stenson, Blair, Salama,
and Lingen along with Drs. Dignam
and Olopade (Cancer Prevention
and Control Program). Patients
with stage III or IV LA-HNC were
treated with carboplatin/paclitaxel
induction chemotherapy followed
by split-course concurrent chemoradiotherapy (CCRT), twice daily
radiotherapy, and gefitinib (250 mg
SORAFENIB SHOWS
EFFICACY IN PATIENTS WITH
PULMONARY ARTERIAL
HYPERTENSION (INTRA/
INTERPROGRAMMATIC)
Cancer and pulmonary arterial
hypertension (PAH) share elements
of pathophysiology, which presents
an opportunity for the cross-development of anticancer agents. Mark
Ratain, MD, Michael Maitland,
MD, PhD, and Stephen Archer,
MD (Advanced Imaging Program)
performed an open-label study of
sorafenib, a multi-kinase/angiogenesis inhibitor, in patients with
pulmonary arterial hypertension
(PAH) for 16 weeks. Patients (n=12)
received 200 mg daily sorafenib with
weekly clinical safety evaluations
and monthly functional testing to
guide dose escalations to 400 mg
twice daily. A dosing regimen of 200
mg sorafenib twice daily was welltolerated in PAH patients with the
most common adverse events being
skin reactions and alopecia. (Gomberg-Maitland et al., Clin Pharmacol
Ther 87:303-10, 2010)
RACIAL DISPARITIES ARE
OBSERVED IN CHILDREN
WITH NEUROBLASTOMA
(INTRAPROGRAMMATIC)
Little is known about the racial and
ethnic disparities that occur in pediatric patients with neuroblastoma.
Susan Cohn, MD, and Tara Henderson, MD, MPH (Cancer Prevention
and Control Program), analyzed
data collected from 3,539 children
enrolled on the Children’s Oncology
Group (COG) neuroblastoma protocol
to evaluate the relationship between
ethnicity, tumor biology, and
survival. Results indicated that black
and Native American patients have
a higher prevalence of high-risk
neuroblastoma. In addition, a higher
prevalence of late-occurring events
among blacks compared with whites
was observed, suggesting that this
population may be more resistant
to chemotherapy. (Henderson et al.,
J Clin Oncol 29:76-82, 2010)
EXPRESSION QUANTITATIVE
TRAIT LOCI ARE
DISCOVERED IN HUMAN
LIVER TISSUE (INTRA/
INTERPROGRAMMATIC)
The reproducibility of expression
quantitative trait loci (eQTL) studies
is largely unknown in primary
tissues. Federico Innocenti, MD,
PhD, Mark Ratain, MD, and Nancy
Cox, PhD (Cancer Prevention
and Control Program), performed
a three-way replication study of
eQTLs in primary human livers
and found hundreds of reproducible
liver eQTLs, many of which are
related directly to complex traits and
connected with disease-associated
loci. Numerous variables were
found to influence reproducibility,
including drug exposure, clinical
descriptors, and factors associated
with tissue ascertainment. The
data will facilitate future efforts to
identify and functionally characterize genetic contributions to complex
traits. (Innocenti et al., PLoS Genet
7:e1002078, 2011)
UCCCC SCIENTIFIC REPORT 2010 – 2011
M. Eileen Dolan, PhD, R. Stephanie
Huang, PhD, and Nancy Cox, PhD
(Cancer Prevention and Control
Program), evaluated the genomic
regions and functional categories
for single nucleotide polymorphisms
(SNPs) associated with chemotherapeutic agent-induced cytotoxicity for
six anticancer agents. These SNPs
were enriched in expression quantitative trait loci (i.e., SNPs associated
with baseline gene expression) with
even greater enrichment of master
regulators (i.e., SNPs associated
with baseline gene expression of 10
or more genes). This observation
has significant implications for the
identification of genetic predictors of
drug response and implies regulatory
genetic variants are most important
for sensitivity to chemotherapeutic
agents. (Gamazon et al., PNAS
107:9287-92, 2010)
daily), an epidermal growth factor
receptor inhibitor for 2 years total.
Among the 69 patients enrolled, the
complete response rate was 90%, and
the 4-year overall survival rate was
74%. However, high EGFR gene
copy number may be associated with
poor outcome in patients treated
with this regimen. (Cohen et al.,
J Clin Oncol 28:3336-43, 2010)
Pharmacogenomics and Experimental Therapeutics
Publications
FUNCTIONAL EGFR GERMLINE
POLYMORPHISMS CONFER
RISK FOR EGFR SOMATIC
MUTATIONS IN NON-SMALL
CELL LUNG CANCER
(INTERPROGRAMMATIC)
Somatic mutations in the EGFR
tyrosine kinase domain are predictive
71
Pharmacogenomics and Experimental Therapeutics
UCCCC SCIENTIFIC REPORT 2010 – 2011
biomarkers for clinical response of
non-small cell lung cancer (NSCLC)
to EGFR inhibitors. Mark Ratain,
MD, and Ravi Salgia, MD, PhD,
(Molecular Mechanisms of Cancer
Program) conducted a case-control
study to elucidate genetic susceptibility to these mutations. Functional
polymorphisms were examined and
found to confer susceptibility to
somatic mutations during cancer
development, particularly those
involving exon 19 microdeletions.
These findings have significant
clinical implications and may shed
light on the pathogenesis of lung
malignancies. (Liu et al., Cancer Res
71:2423-7, 2011)
Grants
RAD51 INHIBITORS MAY
INCREASE SENSITIVITY
TO CHEMOTHERAPY AND
RADIATION THERAPY
Elevated levels of homologous
recombinational (HR) DNA repair
may cause tumor resistance to select
chemotherapies and radiotherapy.
Funded by an R01 grant from the
National Cancer Institute, Philip
Connell, MD, is identifying small
molecule inhibitors of RAD51, a
central protein involved in HR. The
overall goal of this study is to generate
pharmacologic agents that sensitize
human tumors to common oncologic therapies. Given that RAD51
is over-expressed in a wide range of
malignancies, this approach could
potentially improve treatment efficacy
for a large group of cancer patients.
GENOME-WIDE
INTERROGATIONS AIM TO
PREDICT GLUCOCORTICOID
SENSITIVITY
Glucocorticoids are commonly used
for the treatment of cancer and inflammatory diseases including asthma and
arthritis. R. Stephanie Huang, PhD,
72
through support from a National
Institute of General Medical Sciences
K08 award, is making a translational
effort to elucidate the underlying
cause for inter-individual difference in
glucocorticoid sensitivity. Dr. Huang
is applying a novel genome-wide
model, developed using International
HapMap lymphoblastoid cell lines,
to identify genetic polymorphisms
as predictors of cellular sensitivity to
glucocorticoids. The long-term goal is
to predict patients “at risk” for adverse
events and/or non-response prior to
administration of glucocorticoids.
PHARMACOGENETICS OF
ANTICANCER AGENTS
RESEARCH GROUP
EXAMINES GENETIC BASIS OF
CHEMOTHERAPEUTIC DRUG
RESPONSE
Pharmacologic response to anticancer agents is variable and historically
characterized by severe toxicity and
inconsistent efficacy. Mark Ratain,
MD, Nancy J. Cox, PhD, and
M. Eileen Dolan, PhD, successfully renewed a U01 award from
the National Institute of General
Medical Sciences and the National
Cancer Institute to characterize the
genomic basis for this variability
through laboratory and translational
clinical studies that examine targeted
oncology drugs and cytotoxic agents.
Candidate genes identified through
genome-wide clinical studies and
those from HapMap lymphoblastoid
cell lines are being examined for
functional relationships between
drug, gene, and phenotype.
Featured Faculty Profiles††Due to space constraints, only a small representative sample of Program members is presented here.
Instructor of Medicine
Dr. Daniel Catenacci’s laboratory focuses on RON and MET tyrosine kinase
signaling and inhibition strategies in gastroesophageal adenocarcinomas and
other aerodigestive malignancies using in vitro cell culture models, in vivo
murine models, and human tumor and normal tissue samples. Specifically, he
is studying the role of RON and MET receptor tyrosine kinases as biomarkers
of prognosis and as novel therapeutic targets for these diseases. Evaluation of
the structure and function of RON and MET as well as novel small molecule
tyrosine kinase inhibitors and monoclonal antibodies, either as monotherapy
or in combination with other biologically targeted agents and/or chemotherapies, is the primary focus of his laboratory.
In addition, Dr. Catenacci has observed in vitro that MET inhibition can be overcome by
RON cell signaling, given their similar downstream activation pathways. This concept of RONmediated resistance has been supported by a case recently submitted for publication, in a patient
with chemo-refractory metastatic gastric cancer who achieved a complete response to MetMAb,
a monoclonal antibody inhibiting MET signaling, on a phase I protocol. Laboratory correlatives
suggested an autocrine feedback loop given the high tissue expression of HGF (the ligand for
MET) and very high serum levels which decreased after dosing with MetMAb. The complete
response lasted 2 years. Re-challenge with MetMAb therapy after tumor reoccurrence was not
effective. Further studies revealed that RON gene expression and serum levels had become significantly amplified when compared to the original tumor, supporting a RON-mediated resistance
mechanism to MET-directed therapy. Further research is ongoing in the laboratory, and future
clinical trials are being designed to explore this possibility further.
UCCCC SCIENTIFIC REPORT 2010 – 2011
Dr. Catenacci’s recent findings demonstrate that RON is highly over-expressed
in malignant gastroesophageal adenocarcinoma, compared to adjacent
normal mucosa, with a progressive increase in expression from primary tumor
to metastatic lymph node to distant metastases.1 RON is highly oncogenic in
Daniel Catenacci, MD
cell culture models. Moreover, Dr. Catenacci’s laboratory has observed a novel
juxtamembrane mutation in RON in approximately 10% of gastroesophageal
tumor tissues. This mutation increases the stability of RON at the membrane by preventing degradation by CBL ubiquitination. They have also observed increased gene copy number in RON
to high polysomy in approximately 33% of cases evaluated. RON expression and copy number
correlated with a worse overall survival of patients compared to those with low to no expression,
while RON and MET co-expression correlated with the worst survival.
Pharmacogenomics and Experimental Therapeutics
DANIEL CATENACCI, MD
Catenacci DV, Cervantes G, Yala S, Nelson EA, El-Hashani E, Kanteti R, El Dinali M, Hasina R, Brägelmann J, Seiwert T,
Sanicola M, Henderson L, Grushko TA, Olopade O, Karrison T, Bang YJ, Kim WH, Tretiakova M, Vokes E, Frank DA, Kindler HL,
Huet H, Salgia R. RON (MST1R) is a novel prognostic marker and therapeutic target for gastroesophageal adenocarcinoma. Cancer
Biol Ther 12:9-46, 2011.
1
†Due to space constraints, only a small representative sample of Program highlights is presented here. 73
Pharmacogenomics and Experimental Therapeutics
UCCCC SCIENTIFIC REPORT 2010 – 2011
PHILIP CONNELL, MD
Associate Professor of Radiation & Cellular Oncology
Dr. Philip Connell’s laboratory is working to identify molecular targets
that can be exploited in cancer treatment. His work has centered on DNA
repair pathways that are involved in cellular resistance to common cancer
treatments. Specifically, he has focused on proteins involved in homologous
recombination (HR), a pathway involved in the repair of radiation-induced
DNA breaks and chemotherapy-induced DNA cross-links.
The central HR protein, RAD51, is highly expressed in many human cancers
including breast, bladder, prostate, pancreas, soft tissue sarcoma, upper
aerodigestive, and lung. These and other observations suggest that human
tumors may develop “addictions” to abnormally high RAD51 levels. Therefore, RAD51 inhibition represents a promising strategy in oncology drug
development. Dr. Connell’s laboratory is developing small molecules that
inhibit the binding of RAD51 protein to DNA, with the goal of overcoming
treatment resistance in tumors. Furthermore, his group is working to develop
Philip Connell, MD
compounds that stimulate RAD51 protein in normal non-cancerous cells. A
RAD51-stimulatory agent could potentially be used to elevate resistance to
DNA damaging agents in normal tissues, thereby increasing cell survival and perhaps reducing
mutagenesis. This would be an attractive approach for protecting the normal tissues in patients
receiving chemotherapy and/or radiotherapy.
Dr. Connell previously described RS-1, a RAD51-stimulatory compound identified from a highthroughput chemical screen.1 RS-1 was shown to enhance assembly of RAD51 protein filaments
on DNA and to stimulate HR activity in vitro. When introduced into cells in culture, a significant
dose-dependent protection in normal human dermal fibroblasts was achieved. More recently, his
group identified a novel small molecule, termed RI-1, that interrupts RAD51 binding to DNA
and specifically inhibits HR efficiency in human cancer cells. RI-1 significantly sensitizes multiple
human cancer cell lines to mitomycin C. As such, RI-1 will likely be the first reported small
molecule compound that sensitizes cells by directly and specifically disrupting RAD51. Pharmacologic evaluation and testing in animal tumor models will be necessary to define the full
potential of these compounds and related second-generation analogs as drug candidates.
Jayathilaka K, Sheridan SD, Bold TD, Bochenska K, Logan HL, Weichselbaum RR, Bishop DK, Connell PP. A chemical compound
that stimulates the human homologous recombination protein RAD51. PNAS 105:15848-15853, 2008.
1
74
Professor of Chemistry
Dr. Chuan He’s research spans a broad range of chemistry, chemical
biology, microbiology, biochemistry, structural biology, and cell biology.
His laboratory has pioneered research in developing nucleic acid probes
and tools to study the chemistry and mechanism of DNA/RNA repair and
modification systems.
Chuan He, PhD
Dr. He’s group has developed the first high-throughput sequencing method based on a selective chemical labeling strategy to reveal genome-wide distribution of 5-hmC in genomic DNA.1
In addition, Dr. He’s laboratory has presented a detailed mechanistic description of oxidation
demethylation.2 Oxidative demethylation is a key mechanism used in histone and nucleic acid
demethylation, which impact a broad range of cellular processes. The mechanistic understanding
gained from this study may aid future design of new inhibitors for these enzymes.
Song CX, Szulwach KE, Fu Y, Dai Q, Yi C, Li X, Li Y, Chen CH, Zhang W, Jian X, Wang J, Zhang L, Looney TJ, Zhang B, Godley
LA, Hicks LM, Lahn BT, Jin P, He C. Selective chemical labeling reveals the genome-wide distribution of 5-hydroxymethylcytosine.
Nat Biotechnol 29:68-72, 2011.
1
Yi C, Jia G, Hou G, Dai Q, Zhang W, Zheng G, Jian X, Yang CG, Cui Q, He C. Iron-catalysed oxidation intermediates captured
in a DNA repair dioxygenase. Nature 468:330-333, 2010.
2
UCCCC SCIENTIFIC REPORT 2010 – 2011
Dr. He has demonstrated the first example of an active site-based disulfide
cross-linking strategy to successfully isolate covalently linked protein-DNA/
RNA complexes for structural characterization. This general method allows
the stabilization of labile protein-nucleic acid complexes for structural, biochemical, and spectroscopic studies. 5-Hydroxymethylcytosine (5-hmC) is
a newly discovered DNA base modification that has been shown to significantly impact cell development and cell progression. Recently, his laboratory
invented a new strategy to selectively label 5-hmC in genomic DNA. This
method has the potential to significantly broaden the understanding of epigenetics that affect various cellular processes. Overall, Dr. He’s laboratory
strives to integrate chemistry with biology to address major research questions
in life sciences.
Pharmacogenomics and Experimental Therapeutics
CHUAN HE, PHD
75
Pharmacogenomics and Experimental Therapeutics
UCCCC SCIENTIFIC REPORT 2010 – 2011
R. STEPHANIE HUANG, PHD
Assistant Professor of Medicine
Dr. Stephanie Huang’s laboratory focuses on translational pharmacogenomic
research with a specific emphasis on the pharmacogenomics of anticancer
agents. By systematically evaluating the human genomes and their relationships to drug response and toxicity, Dr. Huang’s goal is to develop clinically
useful models that predict risks for adverse drug reactions and non-response
prior to administration of chemotherapy. She utilizes cell lines and clinical
samples to discover and functionally characterize genetic variations, gene, and
microRNA (miRNA) expression for their role in chemotherapeutic sensitivity.
R. Stephanie Huang, PhD
Three major research projects are ongoing in Dr. Huang’s laboratory: 1)
identifying genetic variants, in the form of single nucleotide polymorphisms
(SNPs) and copy number variations (CNVs), that are predictive of sensitivity
to non-cytotoxic chemotherapeutic agents in cell lines and patient samples; 2)
interrogating the role of microRNAs in anticancer agent sensitivity through
integrative genome-wide analyses of genetic variants, transcriptional expression, and drug sensitivity; and 3) developing clinical, user-friendly models for
drug sensitivity screening.
Utilizing a genome-wide, cell-based model, Dr. Huang and colleagues discovered a set of SNPs
that are associated with platinum sensitivity through regulating transcriptional gene expression
in the International HapMap lymphoblastoid cell lines.1 They further validated a subset of these
SNPs in predicting chemotherapeutic outcomes after platinum-based induction therapy in head
and neck cancer patients. To their knowledge, this was the first published work to have successfully reported the validation of genetic predictors from a cell-based, genome-wide model screening
in clinical samples from patients.
Through a genome-wide analysis, Dr. Huang and colleagues identified a set of 33 miRNAs whose
expression levels differ significantly between samples from those with Caucasian ancestry and
those with African ancestry. They further demonstrated the role of genetic variations in these
observed miRNA expression differences, and documented that these differentially expressed
miRNAs can contribute to gene expression and chemotherapeutic sensitivity differences between
Caucasians and Africans.
Ziliak D, O’Donnell PH, Im HK, Gamazon ER, Chen P, Delaney S, Shukla S, Das S, Cox NJ, Vokes EE, Cohen EE, Dolan ME,
Huang RS. Germline polymorphisms discovered via a cell-based, genome-wide approach predict platinum response in head and neck
cancers. Transl Res 157:265-272, 2011.
1
Huang RS, Gamazon ER, Ziliak D, Wen Y, Im HK, Zhang W, Wing C, Duan S, Bleibel WK, Cox NJ, Dolan ME. Population
differences in microRNA expression and biological implications. RNA Biol 8:692-701, 2011.
2
76
Instructor of Medicine
Dr. Peter O’Donnell’s research focuses on translational pharmacogenomics—
achieving individualized patient care by considering each person’s genetic
profile when making therapeutic decisions, especially regarding chemotherapy
choices. He designed and currently oversees three studies with pharmacogenomic primary aims.
In a similar study, Dr. O’Donnell and his collaborators are testing a smaller set of polymorphisms
in a clinical study of 60 patients receiving platinum-based therapy for locally advanced and
metastatic urothelial cancer of the bladder. Since platinum-based therapy can be quite toxic and
result in significant morbidity and mortality for these patients, they hypothesize that validated
genetic “platinum susceptibility” biomarkers will allow the identification of patients with urothelial cancer who will most likely benefit from platinum-based chemotherapy. Dr. O’Donnell has
recently identified several novel platinum sensitivity variants.1
Lastly, Dr. O’Donnell serves as principal investigator of “The 1200 Patients Project,” a first-of-itskind initiative within the Center for Personalized Therapeutics at The University of Chicago, aimed
to explore the feasibility and utility of incorporating broad pharmacogenomic testing into routine
clinical practice. In this study, all known germline pharmacogenomic variants previously published
will be preemptively tested in consenting patients, including cancer patients, to determine whether
pharmacogenomic information can inform prescribing choices by their physicians.
UCCCC SCIENTIFIC REPORT 2010 – 2011
The first is a translational study that proposes to enroll 250 adult women
with breast cancer who will begin treatment with capecitabine, a commonly
used chemotherapeutic agent. Patients will be monitored for manifestation
of any of the three most important capecitabine-related toxicities, including
diarrhea, hand-foot syndrome, or neutropenia. Dr. O’Donnell and his colleagues will screen for approximately 30 top candidate pharmacogenomic
polymorphisms discovered from prior literature and from a recent pre-clinical
cell-based analysis conducted in collaboration with Dr. Eileen Dolan. Specifically, patients’ genotypes will be analyzed for association with capecitabine
Peter H. O’Donnell, MD
toxicity and response, comprising the most comprehensive, prospective
analysis of breast cancer/capecitabine pharmacogenomics to date. This study
will have a large impact on the field and, most importantly, will potentially improve the care of
patients with breast cancer.
Pharmacogenomics and Experimental Therapeutics
PETER H. O’DONNELL, MD
O’Donnell PH, Gamazon E, Zhang W, Stark AL, Kistner-Griffin EO, Huang SR, Dolan EM. Population differences in platinum
toxicity as a means to identify novel genetic susceptibility variants. Pharmacogenet Genomics 20:327-337, 2010.
1
77
Pharmacogenomics and Experimental Therapeutics
UCCCC SCIENTIFIC REPORT 2010 – 2011
78
TANGUY SEIWERT, MD
Assistant Professor of Medicine
Dr. Tanguy Seiwert’s laboratory focuses on elucidating treatment-relevant,
genetic changes in tumors of the head and neck area as well as esophageal
cancers and mesotheliomas. He aims to identify such genetic changes, characterize therapies that specifically target these “driver” aberrations, and translate
findings into clinically relevant treatment concepts and trials in collaboration
with UCCCC clinicians and researchers, including Drs. Ravi Salgia and
Kevin White (Molecular Mechanisms of Cancer Program).
Tanguy Seiwert, MD
Specifically, Dr. Seiwert is detecting genetic changes in cancers using next
generation sequencing technology, array-based approaches, and computational analysis tools. Recently, his team identified aberrations in the
PI3K-AKT signaling pathway in head and neck cancer, where mutations and
other characteristics render tumors exquisitely sensitive to PI3K inhibitors.
In a follow-up study, Dr. Seiwert is conducting a translational clinical trial
that focuses on the treatment of these particular tumors with PI3K inhibitors
previously evaluated in the laboratory.
Furthermore, he is studying how a variety of genetic changes correlate with the efficacy of a large
panel of clinically used drugs in cancer cell line models. Dr. Seiwert’s team employs sophisticated
computational tools to measure the activity of cancer-relevant pathways and evaluate effects of
therapies on these pathways. These studies may enable rapid genetic screening of patients with
head and neck cancers to inform more personalized treatment choices.
Dr. Seiwert’s team has already characterized the important role of c-MET receptor tyrosine kinase
in head and neck cancers in collaboration with Dr. Salgia. As a result, these preclinical discoveries
have led to several clinical initiatives aimed at exploiting c-MET inhibition.
Associate Professor of Pathology
Despite recent advances, improved long-term survival for patients with oral
squamous cell carcinoma (OSCC) has remained modest. Several factors
contribute to this poor outcome. OSCC is often diagnosed during advanced
stages, and as a result of “field cancerization,” the development of multiple
primary tumors has a major impact on survival. For patients with early stage
disease, second primary tumors are the most common cause of treatment
failure and death. Therefore, a comprehensive treatment plan must include
early detection and effective chemoprevention strategies. The induction of
angiogenesis is one of the first recognizable phenotypic changes observed in
both experimental models and in human OSCC. Because of its critical role
in cancer, the inhibition of angiogenesis is an attractive target for therapy.
Furthermore, mounting evidence indicates that inhibitors of angiogenesis are
effective chemopreventive agents against a number of different malignancies.
While resistance to cancer therapy is well-appreciated, there are limited data concerning the
mechanisms of resistance to chemopreventive agents. This is a critical issue as chemoprevention
patients are often treated for prolonged periods of time. Therefore, a need exists to prospectively
model mechanisms of chemoprevention-acquired resistance and test hypotheses for monitoring
and overcoming resistance. In the 4-NQO model, 12% of the mice develop ZD6474-acquired
resistance. Dr. Lingen hypothesizes that ZD6474-acquired resistance in the chemoprevention
setting is due to the expression of alternative angiogenesis pathways and the expression of an
epithelial to mesenchymal transition (EMT) phenotype. Using the 4-NQO model, Dr. Lingen’s
laboratory is seeking to identify biomarkers and alternative angiogenesis pathways that are
activated as a result of ZD6474 resistance. These candidates may have potential for use as both
diagnostic beacons of resistance and alternative targets for chemopreventive therapy.
UCCCC SCIENTIFIC REPORT 2010 – 2011
Using the 4-Nitroquinoline 1-Oxide (4-NQO) mouse model, Dr. Mark
Mark Lingen, DDS, PhD
Lingen’s laboratory has demonstrated that ABT-510 (a global inhibitor of
angiogenesis) and ZD6474 (a dual tyrosine kinase inhibitor (TKI) against
EGFR and VEGFR-2) significantly decrease the incidence of dysplasia and OSCC.1,2 These data
support the hypothesis that agents with anti-angiogenic activity may hold promise in OSCC
chemoprevention. In collaboration with Dr. Ezra Cohen, Dr. Lingen is initiating a doubleblinded, placebo-controlled, randomized phase II trial that will assess the pharmacodynamic and
clinical effects of ZD6474 in patients at high risk for developing OSCC. These results will serve
as proof-of-principle to implement larger prospective chemoprevention trials of anti-angiogenic or
anti-EGFR inhibitors in high-risk patients.
Pharmacogenomics and Experimental Therapeutics
MARK LINGEN, DDS, PHD
Hasina R, Martin LE, Jones C, Jalil A, Lingen MW. ABT-510 is an effective chemopreventive agent in the 4NQO mouse model of
oral carcinogenesis. Cancer Prev Res 2:385-393, 2009.
1
Zhou G, Hasina R, Wroblewski K, Mankame TP, Doci CL, Lingen MW. Dual inhibition of VEGFR and EGFR is an effective
chemopreventive strategy in the mouse 4NQO model of oral carcinogenesis. Cancer Prev Res 3:1493-1502, 2010.
2
79
Selected Publications
UCCCC SCIENTIFIC REPORT 2010 – 2011
Pharmacogenomics and Experimental Therapeutics
* : Intraprogrammatic Collaboration
# : Interprogrammatic Collaboration
BISHOP, DOUGLAS, PHD
Qing Y, Yamazoe M, Hirota K, Dejsuphong D, Sakai W, Yamamoto KN,
Bishop DK, Wu X, Takeda S. The epistatic
relationship between BRCA2 and the
other RAD51 mediators in homologous
recombination. PLoS Genet 7:e1002148,
2011. PMC3136442
Shah PP, Zheng X, Epshtein A, Carey JN,
Bishop DK, Klein HL. Swi2/Snf2-related
translocases prevent accumulation of toxic
Rad51 complexes during mitotic growth.
Mol Cell 39:862-72, 2010. PMC2946244
BLAIR, ELIZABETH, MD
* Mouw KW, Haraf DJ, Stenson KM,
Cohen EE, Xi X, Witt ME, List M,
Blair EA, Vokes EE, Salama JK. Factors
associated with long-term speech and
swallowing outcomes after chemoradiotherapy for locoregionally advanced head
and neck cancer. Arch Otolaryngol Head
Neck Surg 136:1226-34, 2010.
* Salama JK, Haraf DJ, Stenson KM, Blair
EA, Witt ME, Williams R, Kunnavakkam R, Cohen EE, Seiwert T, Vokes EE.
A randomized phase II study of 5-fluorouracil, hydroxyurea, and twice-daily
radiotherapy compared with bevacizumab
plus 5-fluorouracil, hydroxyurea, and
twice-daily radiotherapy for intermediatestage and T4N0-1 head and neck cancers.
Ann Oncol 22:2304-9, 2011.
* Choe KS, Salama JK, Stenson KM, Blair
EA, Witt ME, Cohen EE, Haraf DJ, Vokes
EE. Adjuvant chemotherapy prior to postoperative concurrent chemoradiotherapy
for locoregionally advanced head and neck
cancer. Radiother Oncol 97:318-21, 2010.
* Villaflor VM, Haraf D, Salama JK,
Kocherginsky M, Langerman A, GomezAbuin G, Beniwal P, Blair EA, Stenson
KM, Portugal L, Seiwert T, Williams RD,
Dekker AJ, Witt ME, Vokes EE, Cohen
EE. Phase II trial of pemetrexed-based
induction chemotherapy followed by
concomitant chemoradiotherapy in previously irradiated patients with squamous
cell carcinoma of the head and neck. Ann
Oncol 22:2501-7, 2011.
* Choe KS, Haraf DJ, Solanki A, Cohen
EE, Seiwert TY, Stenson KM, Blair EA,
Portugal L, Villaflor VM, Witt ME, Vokes
EE, Salama JK. Prior chemoradiotherapy
80
adversely impacts outcomes of recurrent
and second primary head and neck cancer
treated with concurrent chemotherapy
and reirradiation. Cancer, 2011 (Epub
ahead of print).
* Pederson AW, Haraf DJ, Witt ME,
Stenson KM, Vokes EE, Blair EA, Salama
JK. Chemoradiotherapy for locoregionally
advanced squamous cell carcinoma of the
base of tongue. Head Neck 32:1519-27, 2010.
Cipriani NA, Blair E, Taxy JB. WHIM
syndrome and oral squamous cell carcinoma. Oral Surg Oral Med Oral Pathol
Oral Radiol Endod 109:105-8, 2010.
* # Cohen EE, Haraf DJ, Kunnavakkam
R, Stenson KM, Blair EA, Brockstein B,
Lester EP, Salama JK, Dekker A, Williams
R, Witt ME, Grushko TA, Dignam
JJ, Lingen MW, Olopade OI, Vokes
EE. Epidermal growth factor receptor
inhibitor gefitinib added to chemoradiotherapy in locally advanced head and neck
cancer. J Clin Oncol 28:3336-43, 2010.
PMC2903330
Rini BI, Schiller JH, Fruehauf JP, Cohen
EE, Tarazi JC, Rosbrook B, Bair AH,
Ricart AD, Olszanski AJ, Letrent KJ,
Kim S, Rixe O. Diastolic blood pressure
as a biomarker of axitinib efficacy in solid
tumors. Clin Cancer Res 17:3841-9, 2011.
Chung CH, Seeley EH, Roder H, Grigorieva J, Tsypin M, Roder J, Burtness BA,
Argiris A, Forastiere AA, Gilbert J, Murphy
B, Caprioli RM, Carbone DP, Cohen EE.
Detection of tumor epidermal growth
factor receptor pathway dependence
by serum mass spectrometry in cancer
patients. Cancer Epidemiol Biomarkers
Prev 19:358-65, 2010. PMC2846615
CATENACCI, DANIEL, MD
# Rothenberg SM, Mohapatra G, Rivera
MN, Winokur D, Greninger P, Nitta M,
Sadow PM, Sooriyakumar G, Brannigan
BW, Ulman MJ, Perera RM, Wang R, Tam
A, Ma XJ, Erlander M, Sgroi DC, Rocco
JW, Lingen MW, Cohen EE, Louis DN,
Settleman J, Haber DA. A genome-wide
screen for microdeletions reveals disruption of polarity complex genes in diverse
human cancers. Cancer Res 70:2158-64,
2010. PMC2881662
Stricker T, Catenacci DV, Seiwert TY.
Molecular profiling of cancer--the future
of personalized cancer medicine: a primer
on cancer biology and the tools necessary
to bring molecular testing to the clinic.
Semin Oncol 38:173-85, 2011.
* Kuo WL, Liu J, Mauceri H, Vokes EE,
Weichselbaum R, Rosner MR, Cohen
EE. Efficacy of the multi-kinase inhibitor enzastaurin is dependent on cellular
signaling context. Mol Cancer Ther
9:2814-24, 2010. PMC2953602
* # Catenacci DV, Cervantes G, Yala S,
Nelson EA, El-Hashani E, Kanteti R,
El Dinali M, Hasina R, Bragelmann J,
Seiwert T, Sanicola M, Henderson L,
Grushko TA, Olopade O, Karrison T,
Bang YJ, Kim WH, Tretiakova M, Vokes
E, Frank DA, Kindler HL, Huet H, Salgia
R. RON (MST1R) is a novel prognostic
marker and therapeutic target for gastroesophageal adenocarcinoma. Cancer Biol
Ther 12:9-46, 2011. PMC3149873
* Gangadhar TC, Cohen EE, Wu K,
Janisch L, Geary D, Kocherginsky M,
House LK, Ramirez J, Undevia SD,
Maitland ML, Fleming GF, Ratain MJ.
Two drug interaction studies of sirolimus
in combination with sorafenib or sunitinib
in patients with advanced malignancies. Clin Cancer Res 17:1956-63, 2011.
PMC3077032
COHEN, EZRA, MD
* # Kurzrock R, Sherman SI, Ball DW,
Forastiere AA, Cohen RB, Mehra R,
Pfister DG, Cohen EE, Janisch L,
Nauling F, Hong DS, Ng CS, Ye L, Gagel
RF, Frye J, Muller T, Ratain MJ, Salgia R.
Activity of XL184 (Cabozantinib), an oral
tyrosine kinase inhibitor, in patients with
medullary thyroid cancer. J Clin Oncol
29:2660-6, 2011.
* # Cohen EE, Haraf DJ, Kunnavakkam
R, Stenson KM, Blair EA, Brockstein B,
Lester EP, Salama JK, Dekker A, Williams
R, Witt ME, Grushko TA, Dignam
JJ, Lingen MW, Olopade OI, Vokes
EE. Epidermal growth factor receptor
inhibitor gefitinib added to chemoradiotherapy in locally advanced head and neck
cancer. J Clin Oncol 28:3336-43, 2010.
PMC2903330
* Choong NW, Kozloff M, Taber D, Hu
HS, Wade J 3rd, Ivy P, Karrison TG,
Dekker A, Vokes EE, Cohen EE. Phase II
study of sunitinib malate in head and neck
squamous cell carcinoma. Invest New
Drugs 28:677-83, 2010.
COHN, SUSAN, MD
Chlenski A, Guerrero LJ, Peddinti R,
Spitz JA, Leonhardt PT, Yang Q, Tian Y,
Salwen HR, Cohn SL. Anti-angiogenic
SPARC peptides inhibit progression of
neuroblastoma tumors. Mol Cancer 9:138,
2010. PMC2895596
Bagatell R, London WB, Wagner
LM, Voss SD, Stewart CF, Maris JM,
Kretschmar C, Cohn SL. Phase II study of
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in MET and EGFR tyrosine kinases. PLoS
One 5:e8972, 2010. PMC2813301
Pharmacogenomics and Experimental Therapeutics
EE. Phase II trial of pemetrexed-based
induction chemotherapy followed by
concomitant chemoradiotherapy in previously irradiated patients with squamous
cell carcinoma of the head and neck. Ann
Oncol 22:2501-7, 2011.
* # Gutt R, Tonlaar N, Kunnavakkam
R, Karrison T, Weichselbaum RR, Liauw
SL. Statin use and risk of prostate cancer
recurrence in men treated with radiation
therapy. J Clin Oncol 28:2653-9, 2010.
# Meng Y, Beckett MA, Liang H, Mauceri
HJ, van Rooijen N, Cohen KS, Weichselbaum RR. Blockade of tumor necrosis
factor alpha signaling in tumor-associated
macrophages as a radiosensitizing strategy.
Cancer Res 70:1534-43, 2010.
* # Barreto-Andrade JC, Efimova EV,
Mauceri HJ, Beckett MA, Sutton HG,
Darga TE, Vokes EE, Posner MC, Kron
SJ, Weichselbaum RR. Response of
91
UCCCC SCIENTIFIC REPORT 2010 – 2011
Pharmacogenomics and Experimental Therapeutics
human prostate cancer cells and tumors to
combining PARP inhibition with ionizing
radiation. Mol Cancer Ther 10:1185-93,
2011. PMC3140695
# Burnette BC, Liang H, Lee Y, Chlewicki
L, Khodarev NN, Weichselbaum RR,
Fu YX, Auh SL. The efficacy of radiotherapy relies upon induction of type i
interferon-dependent innate and adaptive
immunity. Cancer Res 71:2488-96, 2011.
PMC3070872
* Kuo WL, Liu J, Mauceri H, Vokes EE,
Weichselbaum R, Rosner MR, Cohen
EE. Efficacy of the multi-kinase inhibitor enzastaurin is dependent on cellular
signaling context. Mol Cancer Ther
9:2814-24, 2010. PMC2953602
XING, H. ROSIE, PHD
Zhang Q, Bindokas V, Shen J, Fan H,
Hoffman RM, Xing HR. Time-course
imaging of therapeutic functional tumor
vascular normalization by antiangiogenic
agents. Mol Cancer Ther 10:1173-84, 2011.
Xiao H, Zhang Q, Shen J, Bindokas V,
Xing HR. Pharmacologic inactivation
of kinase suppressor of Ras1 sensitizes
epidermal growth factor receptor and
oncogenic Ras-dependent tumors to
ionizing radiation treatment. Mol Cancer
Ther 9:2724-36, 2010.
* # Lee Y, Yang X, Huang Y, Fan H,
Zhang Q, Wu Y, Li J, Hasina R, Cheng
C, Lingen MW, Gerstein MB, Weichselbaum RR, Xing HR, Lussier YA. Network
modeling identifies molecular functions
targeted by miR-204 to suppress head and
neck tumor metastasis. PLoS Comput Biol
6:e1000730, 2010. PMC2848541
* Chen J, Sam L, Huang Y, Lee Y, Li J,
Liu Y, Xing HR, Lussier YA. Protein
interaction network underpins concordant
prognosis among heterogeneous breast
cancer signatures. J Biomed Inform
43:385-96, 2010. PMC2878851
Yu K, Qiu CL, Yang GB, Zong CM, Xing
H, Shao Y, Wei Q, Qin C. Alteration of
serotonin transporter messenger RNA level
in the peripheral blood mononuclear cells
from simian/human immunodeficiency
virus infected Chinese rhesus macaques
(Macaca mulatta). Brain Behav Immun
24:298-305, 2010.
Zhang Q, Yang M, Shen J, Gerhold LM,
Hoffman RM, Xing HR. The role of
the intravascular microenvironment in
spontaneous metastasis development. Int J
Cancer 126:2534-41, 2010.
92
Zhang Q, Fan H, Shen J, Hoffman RM,
Xing HR. Human breast cancer cell lines
co-express neuronal, epithelial, and melanocytic differentiation markers in vitro
and in vivo. PLoS One 5:e9712, 2010.
PMC2838789
Cohn D, Calvert V, Farley J, Petricoin EF,
Birrer MJ. Activity of sorafenib in recurrent ovarian cancer and primary peritoneal
carcinomatosis: a gynecologic oncology
group trial. J Clin Oncol 29:69-75, 2011.
PMC3055861
YAMADA, S. DIANE, MD
YAMINI, BAKHTIAR, MD
De Geest K, Blessing JA, Morris RT, Yamada
SD, Monk BJ, Zweizig SL, Matei D, Muller
CY, Richards WE. Phase II clinical trial of
ixabepilone in patients with recurrent or
persistent platinum- and taxane-resistant
ovarian or primary peritoneal cancer: a
gynecologic oncology group study. J Clin
Oncol 28:149-53, 2010. PMC2799230
* # Nicholas MK, Lukas RV, Chmura S,
Yamini B, Lesniak M, Pytel P. Molecular
heterogeneity in glioblastoma: therapeutic
opportunities and challenges. Semin
Oncol 38:243-53, 2011.
# Zillhardt M, Park SM, Romero IL,
Sawada K, Montag A, Krausz T, Yamada
SD, Peter ME, Lengyel E. Foretinib
(GSK1363089), an orally available multikinase inhibitor of c-Met and VEGFR-2,
blocks proliferation, induces anoikis, and
impairs ovarian cancer metastasis. Clin
Cancer Res 17:4042-51, 2011.
# Kenny HA, Leonhardt P, Ladanyi
A, Yamada SD, Montag A, Im HK,
Jagadeeswaran S, Shaw DE, Mazar AP,
Lengyel E. Targeting the urokinase
plasminogen activator receptor inhibits
ovarian cancer metastasis. Clin Cancer
Res 17:459-71, 2011. PMC3073583
# Hill EK, Sandbo S, Abramsohn E,
Makelarski J, Wroblewski K, Wenrich
ER, McCoy S, Temkin SM, Yamada SD,
Lindau ST. Assessing gynecologic and
breast cancer survivors’ sexual health care
needs. Cancer 117:2643-51, 2011.
Dizon DS, Sill MW, Gould N, Rubin SC,
Yamada SD, Debernardo RL, Mannel RS,
Eisenhauer EL, Duska LR, Fracasso PM.
Phase I feasibility study of intraperitoneal cisplatin and intravenous paclitaxel
followed by intraperitoneal paclitaxel in
untreated ovarian, fallopian tube, and
primary peritoneal carcinoma: A gynecologic oncology group study. Gynecol
Oncol 123:182-6, 2011.
Morgan MA, Sill MW, Fujiwara K,
Greer B, Rubin SC, Degeest K, Yamada
SD, Waggoner S, Coleman RL, Walker
JL, Mannel RS. A phase I study with an
expanded cohort to assess the feasibility
of intraperitoneal carboplatin and intravenous paclitaxel in untreated ovarian,
fallopian tube, and primary peritoneal
carcinoma: A Gynecologic Oncology
Group study. Gynecol Oncol 121:264-8,
2011. PMC3081997
Matei D, Sill MW, Lankes HA, DeGeest
K, Bristow RE, Mutch D, Yamada SD,
YUAN, CHUN-SU, MD, PHD
Qi LW, Wang CZ, Du GJ, Zhang ZY,
Calway T, Yuan CS. Metabolism of ginseng
and its interactions with drugs. Curr Drug
Metab, 2011 (Epub ahead of print).
Xie JT, Du GJ, McEntee E, Aung HH,
He H, Mehendale SR, Wang CZ, Yuan
CS. Effects of triterpenoid glycosides from
fresh ginseng berry on SW480 human
colorectal cancer cell line. Cancer Res
Treat 43:49-55, 2011. PMC3072535
Qi LW, Wang CZ, Yuan CS. Ginsenosides
from American ginseng: chemical and
pharmacological diversity. Phytochemistry 72:689-99, 2011. PMC3103855
Sun S, Qi LW, Du GJ, Mehendale SR,
Wang CZ, Yuan CS. Red notoginseng:
higher ginsenoside content and stronger
anticancer potential than Asian and
American ginseng. Food Chem 125:12991305, 2011. PMC3041968
Qi LW, Wang CZ, Yuan CS. Isolation and
analysis of ginseng: advances and challenges. Nat Prod Rep 28:467-95, 2011.
PMC3056508
# Li B, Zhao J, Wang CZ, Searle J, He
TC, Yuan CS, Du W. Ginsenoside Rh2
induces apoptosis and paraptosis-like cell
death in colorectal cancer cells through
activation of p53. Cancer Lett 301:185-92,
2011. PMC3022099
# Li B, Wang CZ, He TC, Yuan CS, Du
W. Antioxidants potentiate American
ginseng-induced killing of colorectal
cancer cells. Cancer Lett 289:62-70, 2010.
PMC2824022
Du GJ, Dai Q, Williams S, Wang CZ,
Yuan CS. Synthesis of protopanaxadiol
derivatives and evaluation of their anticancer activities. Anticancer Drugs 22:35-45,
2011. PMC2992804
Qi LW, Wang CZ, Yuan CS. American
ginseng: potential structure-function
relationship in cancer chemoprevention.
Biochem Pharmacol 80:947-54, 2010.
Selected Major Grants and Awards
PROJECT
START
DATE
END DATE
EZRA COHEN
A phase 1b trial of LY2584702 in combination
with erlotinib or everolimus in patients with
solid tumors
3/24/2010
3/23/2012
EZRA COHEN
Randomized phase II trial of everolimus versus
placebo as adjuvant therapy in patietns with
locally advanced squamous cell cancer of the
head and neck
3/1/2010
EZRA COHEN
Phase II study of cetuximab and lenalidomide
in recurrent/metastatic squamous cell
carcinoma of the head and neck
EZRA COHEN
INVESTIGATOR
TITLE
TOTAL
ANNUAL
COST
FUNDING AGENCY
$479,400
N/A
Lilly, Eli & Company
12/31/2015
$204,883
N/A
Novartis
Pharmaceuticals
Corporation
1/22/2010
1/21/2012
$157,500
N/A
Celgene
Corporation
Selection of chemoradiotherapy based on
response to induction chemotherapy — a
randomized phase 2 study in locally advanced
squamous cell carcinoma of the head and neck
4/1/2010
12/31/2015
$125,000
N/A
Novartis
Pharmaceuticals
Corporation
SUSAN COHN
Racial and ethnic disparities in survival in
children with neuroblastoma
7/1/2011
6/30/2013
$100,000
N/A
Alex's Lemonade
Stand Foundation
for Childhood
Cancer
PHILIP P.
CONNELL
RAD51 inhibitors for chemotherapy and
radiation therapy
3/16/2010
1/31/2015
$434,469
R01
National Cancer
Institute
CHUAN HE
Chemistry and mechanism of direct DNA
repair proteins
8/5/2010
7/31/2014
$295,699
R01
National Institutes
of Health
CHUAN HE
Selective recognition of heavy elements by
protein-based reagents
5/15/2010
5/14/2013
$165,000
N/A
Department of
Energy
STEPHANIE R.
HUANG
Genome-wide interrogation of genetic
signatures for glucocorticoid sensitivity
3/1/2010
2/28/2015
$100,666
K08
National Institutes
of Health
MICHAEL
MAITLAND
A phase 1 study evaluating the safety and
pharmacokinetics of ABT-348 as monotherapy,
in combination with carboplatin/gemcitabine
or in combination with docetaxel in subjects
with advanced solid tumors
2/12/2010
2/11/2012
$526,027
N/A
Abbott
Laboratories
MICHAEL
MAITLAND
A randomized, open-label, dose escalation
study of bevacizumab with ambulatory blood
pressure monitoring in previously untreated
patients with advanced non-squamous
non-small cell lung cancer
3/9/2010
3/1/2013
$129,980
N/A
Genentech, Inc.
EDWIN
POSADAS
A phase II, open-label, single-arm
study evaluating the safety, efficacy and
pharmacokinetics of KX2-391 in patients
with bone-metastatic, castration-resistant
prostate cancer who have not received
prior chemotherapy
1/12/2010
1/31/2011
$102,575
N/A
Kinex
Pharmaceuticals
LLC
MARK RATAIN
PAAR-Pharmacogenomics of Anticancer
Agents Research Group
7/16/2010
6/30/2015
$2,000,000
U01
National Institute
of General Medical
Sciences
MARK RATAIN
Clinical therapeutics
7/1/2010
6/30/2015
$245,220
T32
National Institutes
of Health
MARK RATAIN
Building a genomic prescribing system
7/1/2011
6/30/2014
$100,000
N/A
American Society
of Clinical Oncology
RUSSELL
SZMULEWITZ
An open-label study of sipuleucel-T in men with
metastatic castrate resistant prostate cancer
3/10/2010
3/9/2012
$134,767
N/A
Dendreon
Corporation
RUSSELL
SZMULEWITZ
A phase I, open-label study of the safety
and pharmacokinteics of escalalting doses
of DSTP30865 in patients with metastatic
castration resistant prostate cancer
2/9/2011
6/30/2014
$118,618
N/A
Genentech, Inc.
UCCCC SCIENTIFIC REPORT 2010 – 2011
CLASS
Pharmacogenomics and Experimental Therapeutics
The Pharmacogenomics and Experimental Therapeutics Program has a funding base of $15,051,170 in annual total
costs (current as of July 2011). This sum includes $5,720,234 in NCI funding and $3,396,687 in other NIH funding.
Due to space constraints, only selected new awards since January 1, 2010 of $100,000 or greater in annual total costs
are listed here.
93
ADVANCED IMAGING
PROGRAM LEADERS
Gregory Karczmar, PhD
Professor of Radiology
94
Heber MacMahon,
MB, ChB
Professor of Radiology
HE
A DVA N CE D
extraordinary
forefront
of
I M AG I N G
advances
the
that
imaging
P RO G R A M
place
revolution
the
that
IS
UCCCC
is
M A K I N G at
the
transforming
cancer care. Imaging resources at the UCCCC are broad and
include
X-ray,
ultrasound,
magnetic
resonance,
molecular
Advanced Imaging
T
imaging, physiological modeling, and quantitative image analysis.
The Program consists of 29 members from five departments who
conduct both pre-clinical and clinical imaging studies using animal
models of disease, cells, tissues, and patients. These members
develop strong collaborations with cancer biologists and oncologists to translate new imaging technologies to the clinical arena.
Research in the Advanced Imaging Program is focused on several
image-guided therapy, and image analysis; 2) development
of targeted contrast agents; 3) early diagnosis of cancer;
4) applications of imaging to guide pre-clinical and clinical drug
development; and 5) use of imaging to study cancer initiation
and progression.
TO AC H I E V E T H E S E G OA L S , R E S E A R C H E R S I N T H E A DVA N C E D
I M AG I N G P R O G R A M A R E A P P LY I N G I M AG I N G M E T H O D S TO :
UCCCC SCIENTIFIC REPORT 2010 – 2011
interlinked areas: 1) development of new technology for imaging,
в– в– Increase the understanding of cancer initiation
and progression;
в– в– Provide non-invasively measured parameters that correlate
with biomarkers;
в– в– Improve early detection and risk assessment of cancer by
developing new approaches to imaging and image analysis;
в– в– Detect response to therapy in clinical trials and develop
image-guided therapies; and
в– в– Evaluate cancer risk and guide risk-management.
95
UCCCC SCIENTIFIC REPORT 2010 – 2011 Advanced Imaging
PROGRAM MEMBERSHIP†Hiroyuki Abe, MD
Assistant Professor of Radiology
Patrick La Riviere, PhD
Associate Professor of Radiology
Hania Al-Hallaq, PhD
Assistant Professor of Radiation &
Cellular Oncology
Stanley Liauw, MD
Assistant Professor of Radiation &
Cellular Oncology
Daniel Appelbaum, MD
Associate Professor of Radiology
Heber MacMahon, MB, ChB
Professor of Radiology
Stephen Archer, MD
Professor of Medicine
Charles Metz, PhD
Professor of Radiology
Samuel Armato, PhD
Associate Professor of Radiology
ОґGillian Newstead, MB, ChB
Professor of Radiology
Issam Awad, MD
Professor of Surgery
Robert Nishikawa, PhD
Associate Professor of Radiology
Bulent Aydogan, PhD
Associate Professor of Radiation &
Cellular Oncology
Aytekin Oto, MD
Professor of Radiology
Richard Baron, MD
Professor of Radiology
Xiaochun Pan, PhD
Professor of Radiology
Chin-Tu Chen, PhD
Associate Professor of Radiology
Charles Pelizzari, PhD
Associate Professor of Radiation &
Cellular Oncology
Abraham Dachman, MD
Professor of Radiology
Brian Roman, PhD
Assistant Professor of Radiology
Maryellen Giger, PhD
Professor of Radiology
Charlene Sennett, MD
Associate Professor of Radiology
Howard Halpern, MD, PhD
Professor of Radiation & Cellular
Oncology
Kenji Suzuki, PhD
Assistant Professor of Radiology
Yulei Jiang, PhD
Associate Professor of Radiology
Michael Vannier, MD
Professor of Radiology
Chien-Min Kao, PhD
Associate Professor of Radiology
Gregory Karczmar, PhD
Professor of Radiology
Anthony Kossiakoff, PhD
Professor of Biochemistry and
Molecular Biology
†Reflects all Program membership during 2010-2011
Оґ Emeritus
96
Program Highlights††Due to space constraints, only a small representative sample of Program highlights is presented here.
DIFFUSION-WEIGHTED
AND DYNAMIC CONTRASTENHANCED MR IMAGING
DIFFERENTIATE PROSTATE
CANCER (INTRA/
INTERPROGRAMMATIC)
DCE-MR IMAGING AIDS
IN CLASSIFICATION OF
BREAST LESIONS
(INTRAPROGRAMMATIC)
Dynamic contrast material-enhanced
(DCE) magnetic resonance (MR)
imaging enables the differentiation of
lesions from normal tissue. Maryellen
Giger, PhD, and Gillian Newstead,
MB, ChB, assessed the performance
of DCE-MR in the differentiation
of invasive and metastatic breast
lesions in a retrospective study using
a breast MR imaging database.
Significant differences in the area
under the receiver operating characteristic curve (AUCs) indicate that
DCE-MR imaging has the potential
to aid in the classification of noninvasive and invasive lesions, and also
discriminate between metastatic and
non-metastatic lesions. (Bhooshan et
al., Radiology 254:680-90, 2010)
VEGF SPATIALLY
CORRELATES WITH PO2
IMAGES IN TUMORS (INTRA/
INTERPROGRAMMATIC)
Tumor microenvironments with
spatially heterogeneous oxygenation
(pO2), can determine the response
to radiation therapy and may allow
early prediction of therapeutic effect.
Howard Halpern, MD, PhD, and
Charles Pelizzari, PhD, along with
Ralph Weichselbaum, MD (Pharmacogenomics and Experimental
Therapeutics Program), designed a
stereotactic delivery system with a
bone biopsy needle to co-localize the
biopsy location in the tumor with
UCCCC SCIENTIFIC REPORT 2010 – 2011
Central gland carcinoma, which
accounts for 30% of all prostate
cancers, can potentially be treated by
image-guided biopsy procedures and
focal therapy if detected and localized
accurately. Aytekin Oto, MD, Yulei
Jiang, PhD, and Greg Karczmar,
PhD, in collaboration with Walter
Stadler, MD, and Arieh Shalhav, MD
(Pharmacogenomics and Experimental Therapeutics Program), compared
the diffusion and perfusion parameters of prostatic lesions to determine
their role in differentiating central
gland carcinoma from benign hyperplasia in a retrospective study of 49
patients who underwent preoperative
magnetic resonance imaging with
an endorectal detector. The apparent
diffusion coefficient (ADC) differed
significantly between central gland
carcinoma, stromal hyperplasia foci,
and glandular hyperplasia foci. These
results indicate that the combination
of diffusion-weighted and dynamic
contrast-enhanced MR imaging has
potential to improve the differentiation of central gland carcinoma from
benign prostatic hyperplasia. (Oto et
al., Radiology 257:715-23, 2010)
agents. Bulent Aydogan, PhD, and
Charles Pelizzari, PhD, along with
Steven Chmura, MD, PhD (Molecular Mechanisms of Cancer Program),
investigated the feasibility of using
a 2-deoxy-d-glucose (2-DG) labeled
gold nanoparticle (AuNP-2-DG) as
a functionally targeted CT contrast
agent for obtaining high-resolution
metabolic and anatomic tumor
information in a single CT scan. In
vitro cellular uptake assays showed
significant contrast enhancement in
multiple CT slices in cells incubated
with AuNP-2-DG. These experiments justify further studies to test
the use of AuNP-2-DG as a functional CT contrast agent in radiation
therapy settings. (Li et al., Phys Med
Biol 55:4389-97, 2010)
Advanced Imaging
Publications
AUNP-2-DG FUNCTIONS
AS A CONTRAST AGENT
FOR CT (INTRA/
INTERPROGRAMMATIC)
When an appropriate X-ray contrast
agent is used, computed tomography
(CT) imaging can provide anatomic
and functional information. This
technique, called functional CT,
is not widely used in patient care
because of the lack of ideal contrast
97
Advanced Imaging
the location of electron paramagnetic resonance image voxels. Using
this system, biopsies stereotactically
located in EPR images of pO2 showed
that VEGF levels correlated with local
pO2 in mouse tumors in vivo. These
measurements will eventually allow
individualized delivery of cancer
therapeutics. (Elas et al., Mol Imaging
Biol 13:1107-1113, 2011)
UCCCC SCIENTIFIC REPORT 2010 – 2011 NORMAL BREAST
PARENCHYMAL ENHANCEMENT
CHARACTERISTICS IN DCEMRI VARY BY TISSUE DENSITY
(INTRAPROGRAMMATIC)
Drs. Gillian Newstead, Gregory
Karczmar, and Maryellen Giger
characterized the kinetic and morphological presentation of the normal
breast using DCE-MR imaging
in a large cohort of asymptomatic
women. The goal was to develop
improved predictors of cancer risk and
minimize false-positive results caused
by normal tissue enhancement.
Women under the age of 45 with
increased breast density exhibited an
increased parenchymal enhancement
pattern (PEP) and a higher proportion
of nodular PEP. This study provides
baseline qualitative and quantitative
measurements of normal breast tissue
enhancement. (Jansen et al., Eur
Radiol 21:1374-82, 2011)
Grants
NEW CAD SYSTEM TO
IMPROVE PROSTATE
CANCER DETECTION
The lack of standardized analysis
tools limits accurate, reproducible
cancer detection and widespread
use of MR imaging techniques for
imaging prostate cancer. Aytekin
Oto, MD, received funding from the
Department of Defense to develop
a computer-aided diagnosis (CAD)
system for detection of prostate
98
cancer using multiparametric 1.5-T
MR images. Development of this
innovative CAD system will allow
more accurate localization of prostate
cancer and allow the determination of
its aggressiveness based on non-invasively obtained MR imaging - derived
parameters. Currently, a noninvasive
method to estimate the histologic
aggressiveness of prostate cancer does
not exist.
IMAGE-GUIDED X-RAY
IRRADIATOR SUPPORTS
BIOMEDICAL RESEARCH
Charles Pelizzari, PhD, was awarded
an S10 shared instrumentation
grant from the National Center for
Research Resources to purchase the
Precision X-ray X RAD225Cx Image
Guided Biological Irradiator System
to support modern, high-precision
image-guided experimental X-ray
irradiation of animals and cells. The
Advanced Imaging
device allows investigators to use
low-dose imaging in radiographic
or cone-beam CT scanning mode
to show the position of the animal
prior to experimental dose. Similar
to patient treatment, this enables
irradiation of the targeted region of
anatomy and not elsewhere.
MRI AIDS IN UNDERSTANDING
THE NATURAL HISTORY OF
PRE-INVASIVE BREAST CANCER
CBCT DEVELOPMENTS
TO ENHANCE PROSTATIC
ADAPTIVE RADIOTHERAPY
Image-guided radiotherapy (IGRT)
is a standard practice for clinical
prostate treatment. Adaptive radiotherapy is a recently developed
form of IGRT based on diagnostic
CT images and adjusted according
to images acquired by cone-beam
CT (CBCT) before and during
treatment. However, the quality of
UCCCC SCIENTIFIC REPORT 2010 – 2011
Funded by an R01 grant from
the National Cancer Institute,
Gregory Karczmar, PhD, and
Suzanne Conzen, MD (Molecular
Mechanisms of Cancer Program),
are examining the biology of
mammary intra-epithelial neoplasia
(MIN), an early neoplasia similar
to ductal carcinoma in situ (DCIS)
in humans, using quantitative serial
MR imaging combined with X-ray
fluorescence microscopy and histology. These efforts aim to identify
optimal MR imaging parameters for
detecting various stages of mammary
cancer and MR imaging-detectable
biological markers that differentiate
malignant from benign disease. The
transdisciplinary approach involving imaging and tumor biology
will improve the understanding of
pre-invasive breast cancer, facilitate
the evaluation of therapies targeting early cancers, and identify MR
imaging markers for cancer risk.
CBCT images limits its utilization.
Through support from a Department of Defense grant, Xiaochuan
Pan, PhD, is enhancing the image
quality of CBCT by developing
advanced CBCT reconstruction
algorithms. Improved image quality
will lead to more effective tumor
control with fewer complications to
surrounding tissues.
99
Featured Faculty Profiles††Due to space constraints, only a small representative sample of Program members is presented here.
Advanced Imaging
HIROYUKI ABE, MD
Assistant Professor of Radiology
The clinical research team in the Department of Radiology, Section of Breast
Imaging, is working to improve the diagnostic process for breast cancer
patients. The team utilizes advanced MR imaging techniques along with computerized imaging analysis. Major research efforts are aimed at developing a
clinical decision support (CDS) system for breast cancer on MR imaging.
This CDS system aids physicians’ decision-making by presenting similar
images to those in question. Clinical similarity was determined subjectively
by expert radiologists and by computer image processing algorithms designed
to match the experts’ perceptual characteristics. The goal is to develop a
fully functional CDS system via a hybrid approach that leverages both our
radiologists’ expertise and state-of-the-art computer techniques. The team has
already reported an observer performance study showing improved radiologists’ performance in differentiating between malignant and benign breast
lesions on MR imaging with use of the computerized system.1
UCCCC SCIENTIFIC REPORT 2010 – 2011 Hiroyuki Abe, MD
A second area of focus is the development of a computerized technique for breast
cancer staging that takes into account axillary lymph node status, an important
factor in determining treatment. The technique is based on morphologic criteria established by the
team in a previous clinical study. In a feasibility study, the ability of the computerized scheme to
identify the same axillary lymph nodes on different modalities such as ultrasound and MR imaging
was reported.2 The results revealed that combined multimodality data provide a more robust noninvasive method of lymph node staging.
The team is also working to improve the assessment of surgically excised specimens. A key factor
in successful breast conservation therapy is complete tumor resection, leaving no residual tumor
cells in the breast. In standard practice, excised breast tissue is radiographed to assess whether the
tumor has been completely excised with sufficient margins. Using a high-field (9.4T) MR imaging
system, preliminary results suggest that MR images of specimens may provide superior visualization, allowing for more accurate assessment of the tumor edge and surgical margins.
1 Shimauchi A, Giger ML, Bhooshan N, Lan L, Pesce LL, Lee JK, Abe H, Newstead GM. Evaluation of clinical breast MR imaging
performed with prototype computer-aided diagnosis breast MR imaging workstation: reader study. Radiology 258:696-704, 2011.
2 Meinel LA, Abe H, Bergtholdt M, Ecanow J, Schmidt R, Newstead G. Multi-modality morphological correlation of axillary lymph
nodes. Int J Comput Assist Radiol Surg 5:343-350, 2010.
100
Associate Professor of Radiation & Cellular Oncology
Imaging is accepted as a central component in our fight against cancer. Nonetheless, clinically applicable tumor-specific functional imaging, especially
for the purpose of radiation oncology, is currently very limited. To meet this
challenge, Dr. Bulent Aydogan and his colleagues are developing a novel functionally targeted CT contrast agent using gold nanoparticles that will provide
high-resolution images without the use of additional radioactive agents.
Dr. Aydogan successfully developed, in collaboration with Argonne National Laboratories, a novel
functional CT contrast agent using gold nanoparticles labeled with 2-deoxyglucose (AuNP-DG).
They demonstrated preferential uptake and functional targeting of cancer cells in preliminary in
vitro experiments. Their goal is to demonstrate the feasibility of this novel CT contrast agent in
preclinical imaging. The successful completion of this project will advance the development of a
new set of capabilities in cancer detection by providing unmatched high-resolution anatomical and
functional images in a single CT scan. Such a contrast agent would be valuable in the early detection,
accurate localization, and monitoring of therapeutic response of human cancers.
UCCCC SCIENTIFIC REPORT 2010 – 2011
Gold, because of its high atomic number, significantly attenuates X-rays and
is capable of producing high contrast in a CT scan. The attachment of organic
molecules, such as deoxyglucose, to the surface of the gold nanoparticles can
potentially enhance their preferential uptake by cancer cells. Deoxyglucose
increases specificity for highly glycolytic cells, and a high rate of glycolysis is
a marker for cancer. Consequently, cancer cells will have a higher concentration of gold particles labeled with deoxyglucose, and therefore, show higher
contrast with respect to the surrounding normal tissue in a CT image. A CT
Bulent Aydogan, PhD
scan taken under this condition will provide both anatomical and physiological information of the subject under investigation, hence the term, functional
CT (fCT). This approach offers potential advantages over positron emission tomography (PET)
scans, such as eliminating the need for radioactive tracers and offering the superior spatial resolution of CT scans, which is essential for tumor definition and targeting as well as early detection
of cancer.
Advanced Imaging
BULENT AYDOGAN, PHD
101
Advanced Imaging
UCCCC SCIENTIFIC REPORT 2010 – 2011 102
GREGORY KARCZMAR, PHD
Professor of Radiology
Work in the Florsheim Magnetic Resonance Imaging/Spectroscopy (MRIS)
laboratory focuses on the development and validation of quantitative MR
imaging methods and the use of those methods for early diagnosis and noninvasive evaluation of response to therapy. In addition, quantitative MRI is
used in the pre-clinical setting to study initiation and progression of early
mammary, prostate, and GI cancers. The laboratory is also involved in the
development of new approaches to MR imaging-guided therapy. Several
advances in the development and application of quantitative functional MR
imaging have been made recently.
The laboratory has developed a new approach to calculating local contrast
agent arterial input function.1 The arterial input function is inferred from the
dynamics of contrast agent in local reference tissues (e.g., muscle) with wellknown pharmacokinetic properties, and combined with measurements of
contrast media washout in an artery. This approach allows correction of perfuGregory Karczmar, PhD
sion measurements to remove variability due to contrast media dose, injection
speed, cardiac output, and other systemic factors. As a result, error in measurements of perfusion and capillary permeability are greatly reduced, resulting in increased sensitivity
to tumor vasculature and changes in vascular function during therapy.
Quantitative MR imaging methods were used to evaluate DCE-MRI data from suspicious breast
lesions acquired with high temporal and spatial resolution.2 This pilot study demonstrated the
feasibility of quantitative analysis of early contrast kinetics at high temporal resolution and points
to the potential for such analysis to improve the characterization of DCIS.
1 Fan X, Haney CR, Mustafi D, Yang C, Zamora M, Markiewicz EJ, Karczmar GS. Use of a reference tissue and blood vessel to
measure the arterial input function in DCEMRI. Magn Reson Med 64:1821-1826, 2010.
2 Jansen SA, Fan X, Medved M, Abe H, Shimauchi A, Yang C, Zamora M, Foxley S, Olopade OI, Karczmar GS, Newstead GM.
Characterizing early contrast uptake of ductal carcinoma in situ with high temporal resolution dynamic contrast-enhanced MRI of the
breast: a pilot study. Phys Med Biol 55:N473-485, 2010.
Professor of Radiology
A need exists for a more efficient and cost-effective diagnosis and management algorithm for prostate cancer patients. Currently, MR imaging is the
best tool for prostate imaging, but its utilization has limitations. Dr. Aytekin
Oto’s primary research focuses on MR imaging of prostate cancer with
specific aims to 1) develop and optimize prostate MR imaging protocols; 2)
improve MR image interpretation by establishing better MR imaging and histopathological correlation and developing computer-aided diagnosis software
to assist radiologists in the interpretation of prostate MR imaging images;
and 3) develop and improve MR imaging-guided focal therapy methods for
prostate cancer, such as laser or high-frequency ultrasound tumor ablation.
Dr. Oto’s work has shown that novel MR imaging techniques, such as diffusion-weighted imaging
(DWI) and DCE imaging, can improve the diagnosis of central gland cancer which comprises
30% of all prostate cancers.1 His research has also demonstrated that apparent diffusion coefficient values (ADC) calculated by DWI correlate with the Gleason Score and, therefore, the
biologic aggressiveness of prostate cancer. Assessment of prostate cancer aggressiveness can aid
in the stratification of patients and identification of appropriate treatments. In addition, Dr. Oto
has successfully led a clinical trial to perform focal therapy for prostate cancer in nine patients,
an emerging treatment using MR imaging-guided laser ablation. He has introduced routine use
of MR-guided prostate biopsies. In collaboration with Philips Healthcare, he is also developing
high-frequency ultrasound ablation of prostate tissues.
UCCCC SCIENTIFIC REPORT 2010 – 2011
During the last 4 years, the Radiology Department has established a busy
prostate MR imaging practice at The University of Chicago Medical Center
with excellent collaboration among colleagues in urology (Drs. Arieh Shalhav
and Scott Eggener), medical oncology (Dr. Walter Stadler), pathology, radiaAytekin Oto, MD
tion oncology (Dr. Stanley Liauw) and medical physicists (Drs. Maryellen
Geiger, Gregory Karczmar, and Yulei Jiang) in the department. Through
these collaborations, the department has received several grants for prostate MR imaging,
including those from the UCCCC, industry (Philips Healthcare, Invivo Corporation, Visualase
Corporation), foundations (American Cancer Society Illinois Division, Admetech Foundation,
Partnership for a Cure Foundation), and a federal institution (Department of Defense).
Advanced Imaging
AYTEKIN OTO, MD
Oto A, Kayhan A, Jiang Y, Tretiakova M, Yang C, Antic T, Dahi F, Shalhav AL, Karczmar G, Stadler WM. Prostate cancer:
differentiation of central gland cancer from benign prostatic hyperplasia by using diffusion-weighted and dynamic contrast-enhanced
MR imaging. Radiology 257:715-723, 2010.
1
103
UCCCC SCIENTIFIC REPORT 2010 – 2011 Advanced Imaging
KENJI SUZUKI, PHD
Assistant Professor of Radiology
Dr. Kenji Suzuki’s laboratory conducts interdisciplinary research in cancer
diagnosis and medical physics, with a primary focus on CAD of lesions in
the abdomen and thorax as well as the development of machine-learning and
pattern-recognition techniques for cancer diagnosis. The long-term goal of
his research is to develop a computer system capable of diagnosing disease
from medical images, similar to how radiologists assist non-expert doctors
with diagnoses. Dr. Suzuki believes that the development of sophisticated
techniques, their theoretical backups, and an understanding of radiologists’
decision-making process and of the human visual system are essential to
achieving this goal. The Suzuki laboratory is making efforts to “weave” the
clinical and technological sciences into a new paradigm that will contribute
to both medicine and medical physics.
Specific aims of Dr. Suzuki’s research are to develop 1) CAD systems for early
detection and accurate diagnosis of lesions in medical images; 2) computerKenji Suzuki, PhD
aided systems for quantifying the characteristics of lesions in medical images;
3) enhanced medical imaging for improving the conspicuity of lesions; and
4) machine-learning and pattern-recognition techniques for detection, diagnosis, quantification,
assessment, and enhancement of lesions in medical images to reduce cancer mortality.
The Suzuki laboratory, in collaboration with Dr. Abraham Dachman, has developed a CAD
system for early detection of polyps (i.e., precursor of colorectal cancer) in CT colonography.
Using a new machine-learning technique developed for false-positive (FP) reduction, the number
of FP detections was reduced by 63% without loss of any true positives. Thus, the FP rate of the
CAD system was improved from 3.1 to 1.1 FPs per patient while maintaining the original sensitivity of 96%.1 By incorporating a new machine-learning model and nonlinear dimension reduction,
the training time of the machine-learning-based FP reduction technique was reduced from 38
hours to 1.2 minutes (by a factor of 1900) while the original performance was maintained.2,3 This
significant improvement in efficiency facilitates the development of CAD schemes based on the
FP reduction technique. In an evaluation of clinical cases from a large multicenter clinical trial,
the CAD system detected 58% of the polyps “missed” by radiologists in CT colonography.4 Thus,
the CAD system has the potential to save 58% of false-negative cases in CT colonography and
potentially reduce colorectal cancer mortality.
Suzuki K, Yoshida H, Nappi J, Armato SG, 3rd, Dachman AH. Mixture of expert 3D massive-training ANNs for reduction of
multiple types of false positives in CAD for detection of polyps in CT colonography. Med Phys 35:694-703, 2008.
1
2 Suzuki K, Zhang J, Xu J. Massive-training artificial neural network coupled with Laplacian-eigenfunction-based dimensionality
reduction for computer-aided detection of polyps in CT colonography. IEEE Trans Med Imaging 29:1907-1917, 2010.
3 Xu J, and Suzuki K. Massive-training support vector regression and Gaussian process for false-positive reduction in computer-aided
detection of polyps in CT colonography. Med Phys 38:1888-1902, 2011.
4
Suzuki K, Rockey DC, Dachman AH. CT colonography: Advanced computer-aided detection scheme utilizing MTANNs for detec-
tion of “missed” polyps in a multicenter clinical trial. Med Phys 30:2-21, 2010.
104
Professor of Radiology
For over 25 years, Dr. Maryellen Giger’s laboratory has been conducting
research in computer-aided diagnosis and quantitative image analysis. Multimodality breast images are acquired and interpreted in the diagnostic work-up
of potential breast cancer cases and in subsequent treatment planning. Dr.
Giger’s research focuses on finding new ways to use computers to help radiologists more effectively and efficiently extract information from medical images
such as mammograms, ultrasound images, and MR images. Her laboratory
develops new methods for manipulating and mining digital breast image data
to yield image-based biomarkers and tumor signatures. Output from such
methods can help characterize tumors, distinguish between cancerous tumors
and benign lesions, assess breast cancer risk, and serve as prognostic and predictive surrogate biomarkers.
In the future, Dr. Giger’s vision is to develop a comprehensive predictive framework for determining novel image-based tumor signatures. This framework would aid in the diagnosis of breast
cancers and facilitate the design of patient-specific, tailored breast cancer treatments, including
initial treatment recommendations and therapy response assessments. Tumor signatures will be
multiscale and multimodality, including attributes of the tumor and its surroundings as well
as systemic contributions. Specifically, they will include computer-extracted macro- and microimaging characteristics (imaging phenotypes), histological classification, molecular classification
(expression), genomics, and clinical presentations. Such a framework will mimic an augmented
electronic tumor board in which contributions from and correlations among clinical, imaging,
pathology, and genomic data will be supplemented by a web-based computer expert system. In
addition, feedback from the relationship between the predictive framework and survival status
will aid in directing future treatment options.
UCCCC SCIENTIFIC REPORT 2010 – 2011
In a collaborative effort between medical physicists and breast radiologists,
Dr. Giger and her colleagues analyzed breast MR images [132 benign, 71
Maryellen Giger, PhD
ductal carcinoma in situ (DCIS), and 150 invasive ductal carcinoma (IDC)
lesions] in the development of image-based prognostic biomarkers.1 Lesion
segmentation and extraction of morphologic and kinetic features were automatically performed by
a laboratory-developed computer workstation. The computer differentiated between DCIS, IDC
lesions, and benign lesions, and also accurately distinguished between IDC lesions associated with
positive lymph nodes (LNs) and those associated with negative LNs. From this study, Dr. Giger
and her colleagues demonstrated that computer-aided diagnosis methods for breast DCE-MR
imaging can be extended from the task of discriminating between malignant and benign lesions
to the prognostic tasks of distinguishing between noninvasive and invasive lesions and between
metastatic and nonmetastatic lesions, yielding MR imaging-based prognostic markers.
Advanced Imaging
MARYELLEN GIGER, PHD
1 Bhooshan N, Giger ML, Jansen SA, Li H, Lan L, Newstead GM. Cancerous breast lesions on dynamic contrast-enhanced MR
images: computerized characterization for image-based prognostic markers. Radiology 254:680-690, 2010.
105
Selected Publications
UCCCC SCIENTIFIC REPORT 2010 – 2011 Advanced Imaging
* : Intraprogrammatic Collaboration
# : Interprogrammatic Collaboration
ABE, HIROYUKI, MD
Shiraishi J, Appelbaum D, Pu Y, Engelmann R, Li Q, Doi K. Clinical utility of
temporal subtraction images in successive
whole-body bone scans: evaluation in a
prospective clinical study. J Digit Imaging
24:680-7, 2011.
* # Medved M, Newstead GM, Abe H,
Olopade OI, Shimauchi A, Zamora MA,
Karczmar GS. Clinical implementation of a multislice high spectral and
spatial resolution-based MRI sequence
to achieve unilateral full-breast coverage.
Magn Reson Imaging 28:16-21, 2010.
PMC2789876
Huang YE, Chen CF, Huang YJ, Konda
SD, Appelbaum DE, Pu Y. Interobserver
variability among measurements of the
maximum and mean standardized uptake
values on (18)F-FDG PET/CT and measurements of tumor size on diagnostic CT
in patients with pulmonary tumors. Acta
Radiol 51:782-8, 2010.
* # Shimauchi A, Jansen SA, Abe H,
Jaskowiak N, Schmidt RA, Newstead
GM. Breast cancers not detected at MRI:
review of false-negative lesions. AJR Am J
Roentgenol 194:1674-9, 2010.
Ilkhchoui Y, Appelbaum DE, Pu Y. FDGPET/CT findings of a metastatic pituitary
tumor. Cancer Imaging 10:114-6, 2010.
Nakayama R, Abe H, Shiraishi J, Doi K.
Evaluation of objective similarity measures
for selecting similar images of mammographic lesions. J Digit Imaging 24:75-85,
2011. PMC3046795
# Gomberg-Maitland M, Maitland ML,
Barst RJ, Sugeng L, Coslet S, Perrino TJ,
Bond L, Lacouture ME, Archer SL, Ratain
MJ. A dosing/cross-development study
of the multikinase inhibitor sorafenib in
patients with pulmonary arterial hypertension. Clin Pharmacol Ther 87:303-10, 2010.
* Abe H, Schmidt RA, Shah RN, Shimauchi A, Kulkarni K, Sennett CA, Newstead
GM. MR-directed (“Second-Look”)
ultrasound examination for breast lesions
detected initially on MRI: MR and sonographic findings. AJR Am J Roentgenol
194:370-7, 2010.
* Shimauchi A, Giger ML, Bhooshan
N, Lan L, Pesce LL, Lee JK, Abe H,
Newstead GM. Evaluation of clinical
breast MR imaging performed with prototype computer-aided diagnosis breast
MR imaging workstation: reader study.
Radiology 258:696-704, 2011.
* # Jansen SA, Fan X, Medved M, Abe H,
Shimauchi A, Yang C, Zamora M, Foxley
S, Olopade OI, Karczmar GS, Newstead
GM. Characterizing early contrast uptake
of ductal carcinoma in situ with high
temporal resolution dynamic contrastenhanced MRI of the breast: a pilot study.
Phys Med Biol 55:N473-85, 2010.
APPELBAUM, DANIEL, MD
Huang YE, Pu YL, Huang YJ, Chen CF,
Pu QH, Konda SD, Appelbaum DE. The
utility of the nonattenuation corrected
18F-FDG PET images in the characteriza
106
tion of solitary pulmonary lesions. Nucl
Med Commun 31:945-51, 2010.
Shiraishi J, Abe H, Ichikawa K, Schmidt
RA, Doi K. Observer study for evaluating
potential utility of a super-high-resolution
LCD in the detection of clustered microcalcifications on digital mammograms.
J Digit Imaging 23:161-9, 2010.
PMC3043779
ARCHER, STEPHEN, MD
ARMATO, SAMUEL, PHD
Corson N, Sensakovic WF, Straus C,
Starkey A, Armato SG 3rd. Characterization of mesothelioma and tissues present
in contrast-enhanced thoracic CT scans.
Med Phys 38:942-7, 2011. PMC3041808
# Sensakovic WF, Armato SG 3rd, Straus
C, Roberts RY, Caligiuri P, Starkey A,
Kindler HL. Computerized segmentation
and measurement of malignant pleural
mesothelioma. Med Phys 38:238-44,
2011. PMC3021556
# Sensakovic WF, Armato SG 3rd,
Starkey A, Kindler HL, Vigneswaran
WT. Quantitative measurement of lung
reexpansion in malignant pleural mesothelioma patients undergoing pleurectomy/
decortication. Acad Radiol 18:294-8,
2011. PMC3075578
* Armato SG 3rd, McLennan G, Hawkins
D, Bidaut L, McNitt-Gray MF, Meyer CR,
Reeves AP, Zhao B, Aberle DR, Henschke
CI, Hoffman EA, Kazerooni EA,
MacMahon H, Van Beeke EJ, Yankelevitz
D, Biancardi AM, Bland PH, Brown MS,
Engelmann RM, Laderach GE, Max D,
Pais RC, Qing DP, Roberts RY, Smith AR,
Starkey A, Batrah P, Caligiuri P, Farooqi
A, Gladish GW, Jude CM, Munden RF,
Petkovska I, Quint LE, Schwartz LH,
Sundaram B, Dodd LE, Fenimore C,
Gur D, Petrick N, Freymann J, Kirby J,
Hughes B, Casteele AV, Gupte S, Sallamm
M, Heath MD, Kuhn MH, Dharaiya E,
Burns R, Fryd DS, Salganicoff M, Anand
V, Shreter U, Vastagh S, Croft BY, Clarke
LP. The Lung Image Database Consortium
(LIDC) and Image Database Resource
Initiative (IDRI): a completed reference
database of lung nodules on CT scans.
Med Phys 38:915-31, 2011. PMC3041807
van Ginneken B, Armato SG 3rd, de
Hoop B, van Amelsvoort-van de Vorst
S, Duindam T, Niemeijer M, Murphy
K, Schilham A, Retico A, Fantacci ME,
Camarlinghi N, Bagagli F, Gori I, Hara T,
Fujita H, Gargano G, Bellotti R, Tangaro
S, Bolanos L, De Carlo F, Cerello P,
Cristian Cheran S, Lopez Torres E, Prokop
M. Comparing and combining algorithms
for computer-aided detection of pulmonary nodules in computed tomography
scans: The ANODE09 study. Med Image
Anal 14:707-22, 2010.
Sensakovic WF, Starkey A, Roberts R,
Straus C, Caligiuri P, Kocherginsky M,
Armato SG 3rd. The influence of initial
outlines on manual segmentation. Med
Phys 37:2153-8, 2010. PMC2874038
AYDOGAN, BULENT, PHD
* # Li J, Chaudhary A, Chmura SJ, Pelizzari C, Rajh T, Wietholt C, Kurtoglu
M, Aydogan B. A novel functional CT
contrast agent for molecular imaging of
cancer. Phys Med Biol 55:4389-97, 2010.
* # Aydogan B, Li J, Rajh T, Chaudhary
A, Chmura SJ, Pelizzari C, Wietholt C,
Kurtoglu M, Redmond P. AuNP-DG:
deoxyglucose-labeled gold nanoparticles
as X-ray computed tomography contrast
agents for cancer imaging. Mol Imaging
Biol 12:463-7, 2010.
Aydogan B, Yeginer M, Kavak GO, Fan J,
Radosevich JA, Gwe-Ya K. Total marrow
irradiation with RapidArc volumetric arc
therapy. Int J Radiat Oncol Biol Phys
81:592-9, 2011.
Yeginer M, Roeske JC, Radosevich JA,
Aydogan B. Linear accelerator-based intensitymodulated total marrow irradiation technique
for treatment of hematologic malignancies:
a dosimetric feasibility study. Int J Radiat
Oncol Biol Phys 79:1256-65, 2011.
Rose BS, Aydogan B, Liang Y, Yeginer
M, Hasselle MD, Dandekar V, Bafana R,
Yashar CM, Mundt AJ, Roeske JC, Mell
LK. Normal tissue complication probability modeling of acute hematologic toxicity
in cervical cancer patients treated with
chemoradiotherapy. Int J Radiat Oncol
Biol Phys 79:800-7, 2011. PMC2907446
BARON, RICHARD, MD
Kim H, Lim JH, Jang KT, Kim MJ, Lee J,
Lee JY, Choi D, Lim HK, Choi DW, Lee
JK, Baron R. Morphology of intraductal
papillary neoplasm of the bile ducts:
radiologic-pathologic correlation. Abdom
Imaging 36:438-46, 2010.
CHEN, CHIN-TU, PHD
# Mathew B, Jacobson JR, Berdyshev E,
Huang Y, Sun X, Zhao Y, Gerhold LM,
Siegler J, Evenoski C, Wang T, Zhou T,
Zaidi R, Moreno-Vinasco L, Bittman R,
Chen CT, Lariviere PJ, Sammani S, Lussier
YA, Dudek SM, Natarajan V, Weichselbaum RR, Garcia JG. Role of sphingolipids
in murine radiation-induced lung injury:
protection by sphingosine 1-phosphate
analogs. FASEB J 25:3388-400, 2011.
# Mathew B, Lennon FE, Siegler J, Mirzapoiazova T, Mambetsariev N, Sammani
S, Gerhold LM, LaRiviere PJ, Chen CT,
Garcia JG, Salgia R, Moss J, Singleton PA.
The novel role of the mu opioid receptor in
lung cancer progression: a laboratory investigation. Anesth Analg 112:558-67, 2011.
* Kim H, Frisch H, Chen CT, Genat JF,
Tang F, Moses WW, Choong WS, Kao
CM. A Design of a PET Detector Using
micro-channel plate photomultipliers with
transmission-line readout. Nucl Instrum
Methods Phys Res A 622:628-636, 2010.
PMC2967035
Souris JS, Lee CH, Cheng SH, Chen CT, Yang
CS, Ho JA, Mou CY, Lo LW. Surface chargemediated rapid hepatobiliary excretion
of mesoporous silica nanoparticles. Biomaterials 31:5564-74, 2010. PMC2875342
Chen LC, Wei CW, Souris JS, Cheng
SH, Chen CT, Yang CS, Li PC, Lo LW.
Enhanced photoacoustic stability of gold
nanorods by silica matrix confinement. J
Biomed Opt 15:016010, 2010.
Rajasekaran S, Kao VY, Chen MR, Yang
AL, Hsu CH, Chen CT, Lin KM. Detection of experimentally induced pulmonary
granuloma inflammation in monocyte
chemoattractant protein-1 reporter mice.
Mol Imaging Biol 12:163-73, 2010.
DACHMAN, ABRAHAM, MD
Dachman AH, Obuchowski NA,
Hoffmeister JW, Hinshaw JL, Frew MI,
Winter TC, Van Uitert RL, Periaswamy S,
Summers RM, Hillman BJ. Effect of computer-aided detection for CT colonography
in a multireader, multicase trial. Radiology
256:827-35, 2010. PMC2923726
Fletcher JG, Chen MH, Herman BA,
Johnson CD, Toledano A, Dachman AH,
Hara AK, Fidler JL, Menias CO, Coakley
KJ, Kuo M, Horton KM, Cheema J,
Iyer R, Siewert B, Yee J, Obregon R,
Zimmerman P, Halvorsen R, Casola G,
Morrin M. Can radiologist training and
testing ensure high performance in CT
colonography? Lessons from the National
CT Colonography Trial. AJR Am J Roentgenol 195:117-25, 2010. PMC3020575
Obuchowski NA, Meziane M, Dachman
AH, Lieber ML, Mazzone PJ. What’s the
control in studies measuring the effect of
computer-aided detection (CAD) on observer
performance? Acad Radiol 17:761-7, 2010.
Suuzuk K, Rockey DC, Dachman AH. CT
colonography: advanced computer-aided
Obuchowski NA, Mazzone PJ, Dachman
AH. Bias, underestimation of risk, and
loss of statistical power in patient-level
analyses of lesion detection. Eur Radiol
20:584-94, 2010.
Hara AK, Kuo MD, Blevins M, Chen MH,
Yee J, Dachman A, Menias CO, Siewert B,
Cheema JI, Obregon RG, Fidler JL, Zimmerman P, Horton KM, Coakley K, Iyer
RB, Halvorsen RA Jr, Casola G, Johnson
CD. National CT colonography trial
(ACRIN 6664): comparison of three fulllaxative bowel preparations in more than
2500 average-risk patients. AJR Am J Roentgenol 196:1076-82, 2011. PMC3144954
Hara AK, Blevins M, Chen MH,
Dachman AH, Kuo MD, Menias CO,
Siewert B, Cheema JI, Obregon RG, Fidler
JL, Zimmerman P, Horton KM, Coakley
KJ, Iyer RB, Halvorsen RA Jr, Casola G,
Yee J, Herman BA, Johnson CD. ACRIN
CT colonography trial: does reader’s
preference for primary two-dimensional
versus primary three-dimensional interpretation affect performance? Radiology
259:435-41, 2011. PMC3079118
* Lostumbo A, Wanamaker C, Tsai J, Suzuki
K, Dachman AH. Comparison of 2D and
3D views for evaluation of flat lesions in CT
colonography. Acad Radiol 17:39-47, 2010.
GIGER, MARYELLEN, PHD
* Chen W, Giger ML, Newstead GM, Bick
U, Jansen SA, Li H, Lan L. Computerized
assessment of breast lesion malignancy
using DCE-MRI robustness study on two
independent clinical datasets from two
manufacturers. Acad Radiol 17:822-9,
2010. PMC2907891
UCCCC SCIENTIFIC REPORT 2010 – 2011
* Oto A, Kulkarni K, Nishikawa R, Baron
RL. Contrast enhancement of hepatic
hemangiomas on multiphase MDCT:
Can we diagnose hepatic hemangiomas by
comparing enhancement with blood pool?
AJR Am J Roentgenol 195:381-386, 2010.
# Mathew B, Huang Y, Jacobson JR,
Berdyshev E, Gerhold LM, Wang T,
Moreno-Vinasco L, Lang G, Zhao Y, Chen
CT, LaRiviere PJ, Mauceri H, Sammani
S, Husain AN, Dudek SM, Natarajan V,
Lussier YA, Weichselbaum RR, Garcia JG.
Simvastatin attenuates radiation-induced
murine lung injury and dysregulated lung
gene expression. Am J Respir Cell Mol
Biol 44:415-22, 2011. PMC3095940
detection scheme utilizing MTANNs for
detection of “missed” polyps in a multicenter clinical trial. Med Phys 37:12-21,
2010. PMC2801730
Advanced Imaging
Tarjan G, Haines GK 3rd, Vesper BJ, Xue J,
Altman MB, Yarmolyuk YR, Khurram H,
Elseth KM, Roeske JC, Aydogan B, Radosevich JA. Part II. Initial molecular and cellular
characterization of high nitric oxide-adapted
human tongue squamous cell carcinoma cell
lines. Tumour Biol 32:87-98, 2011.
Chen MR, Liu SW, Wu TC, Kao VY, Yu
HC, Chen FH, Hsu CH, Chen CT, Lin
KM. RU486-inducible recombination in
the salivary glands of lactoferrin promoterdriven green fluorescent Cre transgenic
mice. Genesis 48:585-95, 2010.
* Chen W, Metz CE, Giger ML, Drukker
K. A novel hybrid linear/nonlinear classifier for two-class classification: theory,
algorithm, and applications. IEEE Trans
Med Imaging 29:428-41, 2010.
* Yuan Y, Giger ML, Li H, Bhooshan N,
Sennett CA. Multimodality computer-aided
breast cancer diagnosis with FFDM and
DCE-MRI. Acad Radiol 17:1158-67, 2010.
Drukker K, Pesce L, Giger M. Repeatability in computer-aided diagnosis:
application to breast cancer diagnosis on
sonography. Med Phys 37:2659-69, 2010.
PMC2885941
107
Advanced Imaging
* Bhooshan N, Giger ML, Jansen SA, Li H,
Lan L, Newstead GM. Cancerous breast
lesions on dynamic contrast-enhanced MR
images: computerized characterization for
image-based prognostic markers. Radiology 254:680-90, 2010. PMC2826695
Seifi P, Epel B, Mailer C, Halpern HJ.
Multiple-stepped Zeeman field offset
method applied in acquiring enhanced
resolution spin-echo electron paramagnetic resonance images. Med Phys
37:5412-20, 2010. PMC2962661
S, Olopade OI, Karczmar GS, Newstead
GM. Characterizing early contrast uptake
of ductal carcinoma in situ with high
temporal resolution dynamic contrastenhanced MRI of the breast: a pilot study.
Phys Med Biol 55:N473-85, 2010.
* Bhooshan N, Giger M, Lan L, Li H,
Marquez A, Shimauchi A, Newstead GM.
Combined use of T(2) -weighted MRI and
T(1) -weighted dynamic contrast-enhanced
MRI in the automated analysis of breast
lesions. Magn Reson Med 66:555-64, 2011.
JIANG, YULEI, PHD
Fan X, Haney CR, Mustafi D, Yang C,
Zamora M, Markiewicz EJ, Karczmar GS.
Use of a reference tissue and blood vessel
to measure the arterial input function in
DCEMRI. Magn Reson Med 64:1821-6,
2010. PMC2992085
UCCCC SCIENTIFIC REPORT 2010 – 2011 * Jansen SA, Lin VC, Giger ML, Li H,
Karczmar GS, Newstead GM. Normal
parenchymal enhancement patterns in
women undergoing MR screening of the
breast. Eur Radiol 21:1374-82, 2011.
* Shimauchi A, Giger ML, Bhooshan
N, Lan L, Pesce LL, Lee JK, Abe H,
Newstead GM. Evaluation of clinical
breast MR imaging performed with prototype computer-aided diagnosis breast
MR imaging workstation: reader study.
Radiology 258:696-704, 2011.
HALPERN, HOWARD, MD, PHD
Epel B, Haney CR, Hleihel D, Wardrip C,
Barth ED, Halpern HJ. Electron paramagnetic resonance oxygen imaging of a rabbit
tumor using localized spin probe delivery.
Med Phys 37:2553-9, 2010. PMC2881926
Burks SR, Macedo LF, Barth ED, Tkaczuk
KH, Martin SS, Rosen GM, Halpern
HJ, Brodie AM, Kao JP. Anti-HER2
immunoliposomes for selective delivery of
electron paramagnetic resonance imaging
probes to HER2-overexpressing breast
tumor cells. Breast Cancer Res Treat
124:121-31, 2010.
* # Elas M, Hleihel D, Barth ED, Haney
CR, Ahn KH, Pelizzari CA, Epel B,
Weichselbaum RR, Halpern HJ. Where
It’s at Really Matters: In Situ In Vivo
Vascular Endothelial Growth Factor
Spatially Correlates with Electron Paramagnetic Resonance pO(2) Images in
Tumors of Living Mice. Mol Imaging
Biol, 2010.
Epel B, Sundramoorthy SV, Barth ED,
Mailer C, Halpern HJ. Comparison of 250
MHz electron spin echo and continuous
wave oxygen EPR imaging methods for in
vivo applications. Med Phys 38:2045-52,
2011. PMC3078157
108
Tseitlin M, Quine RW, Eaton SS, Eaton
GR, Halpern HJ, Ardenkjaer-Larsen
JH. Use of the Frank sequence in pulsed
EPR. J Magn Reson 209:306-9, 2011.
PMC3107679
* Jiang Y, Metz CE. BI-RADS data should
not be used to estimate ROC curves. Radiology 256:29-31, 2010. PMC2897690
Zur RM, Pesce LL, Jiang Y. The effect
of two priors on Bayesian estimation of
“Proper” binormal ROC curves from
common and degenerate datasets. Acad
Radiol 17:969-79, 2010.
* # Oto A, Kayhan A, Jiang Y, Tretiakova
M, Yang C, Antic T, Dahi F, Shalhav
AL, Karczmar G, Stadler WM. Prostate
cancer: differentiation of central gland
cancer from benign prostatic hyperplasia
by using diffusion-weighted and dynamic
contrast-enhanced MR imaging. Radiology 257:715-23, 2010.
KAO, CHIEN-MIN, PHD
* Kim H, Frisch H, Chen CT, Genat JF, Tang
F, Moses WW, Choong WS, Kao CM. A
design of a PET detector using micro-channel
plate photomultipliers with transmission-line
readout. Nucl Instrum Methods Phys Res A
622:628-636, 2010. PMC2967035
KARCZMAR, GREGORY, PHD
* # Jansen SA, Conzen SD, Fan X, Markiewicz E, Krausz T, Newstead GM, Karczmar
GS. In vivo MRI of early stage mammary
cancers and the normal mouse mammary
gland. NMR Biomed 24:880-7, 2011.
* Jansen SA, Shimauchi A, Zak L, Fan X,
Karczmar GS, Newstead GM. The diverse
pathology and kinetics of mass, nonmass,
and focus enhancement on MR imaging
of the breast. J Magn Reson Imaging
33:1382-9, 2011. PMC3098464
* Jansen SA, Lin VC, Giger ML, Li H,
Karczmar GS, Newstead GM. Normal
parenchymal enhancement patterns in
women undergoing MR screening of the
breast. Eur Radiol 21:1374-82, 2011.
* Haney CR, Pelizzari CA, Foxley S,
Zamora MA, Mustafi D, Tretiakova
M, Li S, Fan X, Karczmar GS. HiSStology: high spectral and spatial resolution
magnetic resonance imaging detection
of vasculature validated by histology
and micro-computed tomography. Mol
Imaging 10:187-96, 2011. PMC3079458
* # Jansen SA, Fan X, Medved M, Abe H,
Shimauchi A, Yang C, Zamora M, Foxley
* # Medved M, Ivancevic MK, Olopade OI,
Newstead GM, Karczmar GS. Echo-planar
spectroscopic imaging (EPSI) of the water
resonance structure in human breast using
sensitivity encoding (SENSE). Magn Reson
Med 63:1557-63, 2010. PMC3065325
* # Medved M, Newstead GM, Abe H,
Olopade OI, Shimauchi A, Zamora MA,
Karczmar GS. Clinical implementation of a multislice high spectral and
spatial resolution-based MRI sequence
to achieve unilateral full-breast coverage.
Magn Reson Imaging 28:16-21, 2010.
PMC2789876
LA RIVIERE, PATRICK, PHD
Green AH, Norris JR, Wang J, Xie Z,
Zhang HF, La Riviere PJ. In vitro testing
of a protease-sensitive contrast agent for
optoacoustic imaging. J Biomed Opt
15:021315, 2010.
Modgil D, Anastasio MA, La Riviere PJ.
Image reconstruction in photoacoustic
tomography with variable speed of
sound using a higher-order geometrical
acoustics approximation. J Biomed Opt
15:021308, 2010.
* La Riviere P, Vargas P, Xia D, Pan X.
Region of interest reconstruction in X-ray
fluorescence computed tomography for
negligible attenuation. IEEE Trans Nucl
Sci 57:234-241, 2010. PMC2851101
Petschke A, La Riviere PJ. Comparison
of intensity-modulated continuous-wave
lasers with a chirped modulation frequency
to pulsed lasers for photoacoustic imaging
applications. Biomed Opt Express 1:11881195, 2010. PMC3018082
Forthmann P, Koehler T, Defrise M, La
Riviere P. Comparing implementations of
penalized weighted least-squares sinogram
restoration. Med Phys 37:5929-38, 2010.
PMC2988831
Modgil D, La Riviere PJ. Optimizing
wavelength choice for quantitative optoacoustic imaging using the Cramer-Rao lower
bound. Phys Med Biol 55:7231-51, 2010.
LIAUW, STANLEY, MD
# Gutt R, Tonlaar N, Kunnavakkam R,
Karrison T, Weichselbaum RR, Liauw
SL. Statin use and risk of prostate cancer
recurrence in men treated with radiation
therapy. J Clin Oncol 28:2653-9, 2010.
Terakedis BE, Rossi PJ, Liauw SL,
Johnstone PA, Jani AB. A surveillance, epidemiology, and end results registry analysis
of prostate cancer modality time trends by
age. Am J Clin Oncol 33:619-23, 2010.
Devisetty K, Zorn KC, Katz MH, Jani
AB, Liauw SL. External beam radiation
therapy after transurethral resection of
the prostate: a report on acute and late
genitourinary toxicity. Int J Radiat Oncol
Biol Phys 77:1060-5, 2010.
* Kalakota K, Rakhno E, Pelizzari CA,
Jani AB, Liauw SL. Late rectal toxicity
after prostate brachytherapy: influence of
supplemental external beam radiation on
dose-volume histogram analysis. Brachytherapy 9:131-6, 2010.
Jani AB, Johnstone PA, Liauw SL, Master
VA, Rossi PJ. Prostate cancer modality
time trend analyses from 1973 to 2004:
a Surveillance, Epidemiology, and End
Results registry analysis. Am J Clin Oncol
33:168-72, 2010.
* Pederson AW, Fricano J, Correa D,
Pelizzari CA, Liauw SL. Late toxicity after
intensity-modulated radiation therapy for
localized prostate cancer: An exploration
of dose-volume histogram parameters to
limit genitourinary and gastrointestinal
toxicity. Int J Radiat Oncol Biol Phys,
2010 (Epub ahead of print).
MACMAHON, HEBER, MB, CHB
* Armato SG 3rd, McLennan G, Hawkins
D, Bidaut L, McNitt-Gray MF, Meyer CR,
Reeves AP, Zhao B, Aberle DR, Henschke
CI, Hoffman EA, Kazerooni EA,
MacMahon H, Van Beeke EJ, Yankelevitz
D, Biancardi AM, Bland PH, Brown MS,
Engelmann RM, Laderach GE, Max D,
Pais RC, Qing DP, Roberts RY, Smith AR,
Starkey A, Batrah P, Caligiuri P, Farooqi
Li F, Hara T, Shiraishi J, Engelmann R,
MacMahon H, Doi K. Improved detection
of subtle lung nodules by use of chest radiographs with bone suppression imaging:
receiver operating characteristic analysis
with and without localization. AJR Am J
Roentgenol 196:W535-41, 2011.
Mohammed TL, Chowdhry A, Reddy GP,
Amorosa JK, Brown K, Dyer DS, Ginsburg
ME, Heitkamp DE, Jeudy J, Kirsch J,
MacMahon H, Parker JA, Ravenel JG,
Saleh AG, Shah RD. ACR Appropriateness
Criteria(R) screening for pulmonary metastases. J Thorac Imaging 26:W1-3, 2011.
* Chen S, Suzuki K, MacMahon H.
Development and evaluation of a computer-aided diagnostic scheme for lung
nodule detection in chest radiographs by
means of two-stage nodule enhancement
with support vector classification. Med
Phys 38:1844-58, 2011. PMC3069992
Li F, Engelmann R, Doi K, Macmahon
H. True detection versus “accidental”
detection of small lung cancer by a
computer-aided detection (CAD) program
on chest radiographs. J Digit Imaging
23:66-72, 2010. PMC3043747
METZ, CHARLES, PHD
* Chen W, Metz CE, Giger ML, Drukker
K. A novel hybrid linear/nonlinear classifier for two-class classification: theory,
algorithm, and applications. IEEE Trans
Med Imaging 29:428-41, 2010.
Pesce LL, Metz CE, Berbaum KS. On
the convexity of ROC curves estimated
from radiological test results. Acad Radiol
17:960-968.e4, 2010. PMC2897827
* Jiang Y, Metz CE. BI-RADS data should
not be used to estimate ROC curves. Radiology 256:29-31, 2010. PMC2897690
NEWSTEAD, GILLIAN, MB, CHB
* # Medved M, Newstead GM, Abe H,
Olopade OI, Shimauchi A, Zamora MA,
Karczmar GS. Clinical implementation
of a multislice high spectral and spatial
resolution-based MRI sequence to achieve
unilateral full-breast coverage. Magn Reson
Imaging 28:16-21, 2010. PMC2789876
* # Medved M, Ivancevic MK, Olopade
OI, Newstead GM, Karczmar GS. Echoplanar spectroscopic imaging (EPSI) of
the water resonance structure in human
breast using sensitivity encoding (SENSE).
Magn Reson Med 63:1557-63, 2010.
PMC3065325
* Bhooshan N, Giger ML, Jansen SA, Li H,
Lan L, Newstead GM. Cancerous breast
lesions on dynamic contrast-enhanced MR
images: computerized characterization for
image-based prognostic markers. Radiology 254:680-90, 2010. PMC2826695
# Meinel LA, Buelow T, Huo D, Shimauchi
A, Kose U, Buurman J, Newstead G. Robust
segmentation of mass-lesions in contrastenhanced dynamic breast MR images. J
Magn Reson Imaging 32:110-9, 2010.
* # Jansen SA, Conzen SD, Fan X, Markiewicz E, Krausz T, Newstead GM, Karczmar
GS. In vivo MRI of early stage mammary
cancers and the normal mouse mammary
gland. NMR Biomed 24:880-7, 2011.
* Jansen SA, Shimauchi A, Zak L, Fan X,
Karczmar GS, Newstead GM. The diverse
pathology and kinetics of mass, nonmass,
and focus enhancement on MR imaging
of the breast. J Magn Reson Imaging
33:1382-9, 2011. PMC3098464
* Bhooshan N, Giger M, Lan L, Li H,
Marquez A, Shimauchi A, Newstead GM.
Combined use of T(2) -weighted MRI and
T(1) -weighted dynamic contrast-enhanced
MRI in the automated analysis of breast
lesions. Magn Reson Med 66:555-564, 2011.
UCCCC SCIENTIFIC REPORT 2010 – 2011
# Liauw SL, Stadler WM, Correa D,
Weichselbaum RR, Jani AB. Dose-escalated radiotherapy for high-risk prostate
cancer: outcomes in modern era with
short-term androgen deprivation therapy.
Int J Radiat Oncol Biol Phys 77:125-30,
2010. PMC3049990
A, Gladish GW, Jude CM, Munden RF,
Petkovska I, Quint LE, Schwartz LH,
Sundaram B, Dodd LE, Fenimore C,
Gur D, Petrick N, Freymann J, Kirby J,
Hughes B, Casteele AV, Gupte S, Sallamm
M, Heath MD, Kuhn MH, Dharaiya E,
Burns R, Fryd DS, Salganicoff M, Anand
V, Shreter U, Vastagh S, Croft BY, Clarke
LP. The Lung Image Database Consortium
(LIDC) and Image Database Resource
Initiative (IDRI): a completed reference
database of lung nodules on CT scans.
Med Phys 38:915-31, 2011. PMC3041807
Advanced Imaging
# Gutt R, Liauw SL, Weichselbaum
RR. The role of radiotherapy in locally
advanced pancreatic carcinoma. Nat Rev
Gastroenterol Hepatol 7:437-47, 2010.
* Jansen SA, Lin VC, Giger ML, Li H,
Karczmar GS, Newstead GM. Normal
parenchymal enhancement patterns in
women undergoing MR screening of the
breast. Eur Radiol 21:1374-82, 2011.
NISHIKAWA, ROBERT, PHD
Jing H, Yang Y, Nishikawa RM. Detection of clustered microcalcifications using
spatial point process modeling. Phys Med
Biol 56:1-17, 2011.
* # Oto A, Kulkarni K, Nishikawa R,
Baron RL. Contrast enhancement of
hepatic hemangiomas on multiphase
MDCT: Can we diagnose hepatic hemangiomas by comparing enhancement
with blood pool? AJR Am J Roentgenol
195:381-6, 2010.
Reiser I, Nishikawa RM. Task-based
assessment of breast tomosynthesis: effect
of acquisition parameters and quantum
109
noise. Med Phys 37:1591-600, 2010.
PMC2852443
Advanced Imaging
OTO, AYTEKIN, MD
Kayhan A, Fan X, Oommen J, Oto
A. Multi-parametric MR imaging of
transition zone prostate cancer: Imaging
features, detection and staging. World J
Radiol 2:180-7, 2010. PMC2999020
* # Oto A, Kulkarni K, Nishikawa R,
Baron RL. Contrast enhancement of
hepatic hemangiomas on multiphase
MDCT: Can we diagnose hepatic hemangiomas by comparing enhancement
with blood pool? AJR Am J Roentgenol
195:381-6, 2010.
UCCCC SCIENTIFIC REPORT 2010 – 2011 * # Oto A, Kayhan A, Jiang Y, Tretiakova
M, Yang C, Antic T, Dahi F, Shalhav
AL, Karczmar G, Stadler WM. Prostate
cancer: differentiation of central gland
cancer from benign prostatic hyperplasia
by using diffusion-weighted and dynamic
contrast-enhanced MR imaging. Radiology
257:715-23, 2010.
PAN, XIAOCHUN, PHD
* La Riviere P, Vargas P, Xia D, Pan X.
Region of interest reconstruction in x-ray
fluorescence computed tomography for
negligible attenuation. IEEE Trans Nucl
Sci 57:234-241, 2010. PMC2851101
Han X, Bian J, Eaker DR, Kline TL, Sidky
EY, Ritman EL, Pan X. Algorithm-enabled
low-dose micro-CT imaging. IEEE Trans
Med Imaging 30:606-20, 2011.
* Bian J, Siewerdsen JH, Han X, Sidky EY,
Prince JL, Pelizzari CA, Pan X. Evaluation
of sparse-view reconstruction from flatpanel-detector cone-beam CT. Phys Med
Biol 55:6575-99, 2010.
Bian J, Xia D, Sidky EY, Pan X. Region
of interest imaging for a general trajectory with the rebinned BPF algorithm.
Tsinghua Sci Technol 15:68-73, 2010.
PMC2898485
Cho S, Sidky EY, Bian J, Pan X. Dualenergy technique at low tube voltages
for small animal imaging. Tsinghua Sci
Technol 15:79-86, 2010. PMC2892926
Sidky EY, Anastasio MA, Pan X. Image
reconstruction exploiting object sparsity in
boundary-enhanced X-ray phase-contrast
tomography. Opt Express 18:10404-22,
2010. PMC2987648
Xia D, Cho S, Pan X. Backprojectionfiltration reconstruction without invoking
a spatially varying weighting factor. Med
Phys 37:1201-9, 2010. PMC2837731
110
Cho S, Xia D, Pellizzari CA, Pan X. A
BPF-FBP tandem algorithm for image
reconstruction in reverse helical conebeam CT. Med Phys 37:32-9, 2010.
PMC2801731
PELIZZARI, CHARLES, PHD
* Haney CR, Pelizzari CA, Foxley S,
Zamora MA, Mustafi D, Tretiakova
M, Li S, Fan X, Karczmar GS. HiSStology: high spectral and spatial
resolution magnetic resonance imaging
detection of vasculature validated by
histology and micro-computed tomography. Mol Imaging 10:187-96, 2011.
PMC3079458
* Pederson AW, Fricano J, Correa D,
Pelizzari CA, Liauw SL. Late toxicity after
intensity-modulated radiation therapy for
localized prostate cancer: An exploration
of dose-volume histogram parameters to
limit genitourinary and gastrointestinal
toxicity. Int J Radiat Oncol Biol Phys,
2010 (Epub ahead of print).
* # Elas M, Hleihel D, Barth ED, Haney
CR, Ahn KH, Pelizzari CA, Epel B,
Weichselbaum RR, Halpern HJ. Where
it’s at really matters: In situ in vivo vascular
endothelial growth factor spatially correlates with electron paramagnetic resonance
pO(2) images in tumors of living mice. Mol
Imaging Biol 13:1107-13, 2011.
* Bian J, Siewerdsen JH, Han X, Sidky EY,
Prince JL, Pelizzari CA, Pan X. Evaluation
of sparse-view reconstruction from flatpanel-detector cone-beam CT. Phys Med
Biol 55:6575-99, 2010.
* Kalakota K, Rakhno E, Pelizzari CA,
Jani AB, Liauw SL. Late rectal toxicity
after prostate brachytherapy: influence of
supplemental external beam radiation on
dose-volume histogram analysis. Brachytherapy 9:131-6, 2010.
* # Li J, Chaudhary A, Chmura SJ, Pelizzari C, Rajh T, Wietholt C, Kurtoglu
M, Aydogan B. A novel functional CT
contrast agent for molecular imaging of
cancer. Phys Med Biol 55:4389-97, 2010.
# MacDermed DM, Khodarev NN,
Pitroda SP, Edwards DC, Pelizzari CA,
Huang L, Kufe DW, Weichselbaum RR.
MUC1-associated proliferation signature
predicts outcomes in lung adenocarcinoma
patients. BMC Med Genomics 3:16, 2010.
PMC2876055
* # Aydogan B, Li J, Rajh T, Chaudhary
A, Chmura SJ, Pelizzari C, Wietholt C,
Kurtoglu M, Redmond P. AuNP-DG:
deoxyglucose-labeled gold nanoparticles
as X-ray computed tomography contrast
agents for cancer imaging. Mol Imaging
Biol 12:463-7, 2010.
ROMAN, BRIAN, PHD
Leoni L, Roman BB. MR imaging of
pancreatic islets: tracking isolation, transplantation and function. Curr Pharm Des
16:1582-94, 2010.
SENNETT, CHARLENE, MD
* Yuan Y, Giger ML, Li H, Bhooshan N,
Sennett CA. Multimodality computer-aided
breast cancer diagnosis with FFDM and
DCE-MRI. Acad Radiol 17:1158-67, 2010.
* Abe H, Schmidt RA, Shah RN, Shimauchi A, Kulkarni K, Sennett CA, Newstead
GM. MR-directed (“Second-Look”)
ultrasound examination for breast lesions
detected initially on MRI: MR and sonographic findings. AJR Am J Roentgenol
194:370-7, 2010.
SUZUKI, KENJI, PHD
Suzuki K, Kohlbrenner R, Epstein ML,
Obajuluwa AM, Xu J, Hori M. Computeraided measurement of liver volumes in
CT by means of geodesic active contour
segmentation coupled with level-set
algorithms. Med Phys 37:2159-66, 2010.
PMC2874039
* Lostumbo A, Wanamaker C, Tsai J,
Suzuki K, Dachman AH. Comparison
of 2D and 3D views for evaluation of flat
lesions in CT colonography. Acad Radiol
17:39-47, 2010.
Suzuki K, Zhang J, Xu J. Massive-training
artificial neural network coupled with
Laplacian-eigenfunction-based dimensionality reduction for computer-aided detection
of polyps in CT colonography. IEEE Trans
Med Imaging 29:1907-17, 2010.
Xu JW, Suzuki K. Massive-training
support vector regression and Gaussian
process for false-positive reduction in
computer-aided detection of polyps in CT
colonography. Med Phys 38:1888-902,
2011. PMC3069995
* Chen S, Suzuki K, MacMahon H.
Development and evaluation of a computer-aided diagnostic scheme for lung
nodule detection in chest radiographs by
means of two-stage nodule enhancement
with support vector classification. Med
Phys 38:1844-58, 2011. PMC3069992
Selected Major Grants and Awards
INVESTIGATOR
TITLE
PROJECT
START
DATE
END DATE
TOTAL
ANNUAL
COST
CLASS
FUNDING AGENCY
O2 sensing in the human and rabbit ductus
arteriosus
7/1/2011
4/30/2016
$390,000
R01
National Heart,
Lung, and Blood
Institute
SAMUEL
ARMATO
An image storage and retrieval system for
biomedical imaging research
5/1/2011
4/30/2012
$357,000
S10
National Institutes
of Health
MARYELLEN
GIGER
Research Training in Medical Physics
9/1/2010
8/31/2015
$266,942
T32
National Institutes
of Health
MARYELLEN
GIGER
Somo versus ABUS ROC reader observer study
4/15/2010
1/2/2012
$200,000
N/A
U-Systems, Inc.
GREGORY
KARCZMAR
MRI of early non-invasive rodent mammary
cancers
3/1/2011
12/31/2015
$337,038
R01
National Cancer
Institute
GREGORY
KARCZMAR
Development and clinical evaluation of
MR-guided focused ultrasound for tattooing
tumors to guide radiotherapy as well as other
therapies
8/1/2010
7/31/2011
$100,000
N/A
Focused Ultrasound
Surgery Foundation
PATRICK LA
RIVIERE
High-resolution large field of view ultrasound
breast imager
6/1/2011
5/31/2013
$248,984
N/A
Department of
Defense
PATRICK LA
RIVIERE
X-ray fluorescence tomography with emission
tomography apertures
9/1/2010
8/31/2012
$101,767
R21
National Institute of
Biological Imaging
and Bioengineering
AYTEKIN OTO
Computer-aided diagnosis of prostate cancer
with multi-parametric MR imaging
8/1/2010
8/31/2012
$351,000
N/A
Department of
Defense
XIAOCHUAN
PAN
Targeted imaging in helical cone-beam CT
2/7/2011
1/31/2015
$410,720
R01
National Institute of
Biological Imaging
and Bioengineering
CHARLES
PELIZZARI
Image-guided X-ray irradiator for biomedical
research
8/14/2010
8/13/2011
$423,555
S10
National Institutes
of Health
UCCCC SCIENTIFIC REPORT 2010 – 2011
STEPHEN
ARCHER
Advanced Imaging
The Advanced Imaging Program has a funding base of $10,308,792 in annual total costs (current as of July 2011).
This sum includes $1,576,690 in NCI funding and $5,324,646 in other NIH funding. Due to space constraints, only
selected new awards since January 1, 2010 of $100,000 or greater in annual total costs are listed here.
111
CANCER PREVENTION AND CONTROL
PROGRAM LEADERS
Habibul Ahsan,
MBBS, MMedSc
Professor of
Health Studies
112
Brian Chiu, PhD
Associate Professor of
Health Studies
Andrea King, PhD
Professor of Psychiatry
HE CANCER PREVENTION AND CONTROL PROGRAM IS
determining
the
genetic,
psychological,
behavioral,
and
socio-environmental basis of cancer, and interactions among
these variables. The Program consists of 41 members from 11
departments and two University Divisions (Biological Sciences,
Social Sciences) who focus their research on high-risk individuals
defined by these factors as well as health outcomes, survivorship,
Cancer Prevention and Control
T
and economics. Members emphasize cancer control and molecular
epidemiology research and aim to translate and disseminate their
efforts to the community. The Program is committed to outreach
efforts in South Side Chicago neighborhoods to enhance participation and utilization of University of Chicago research, education,
outcomes, and their modifiable determinants in the community.
THE SCIENTIFIC AIMS OF THE CANCER PREVENTION A N D CO N T R O L P R O G R A M A R E TO :
в– в– Identify novel genomic, nutritional, and
environmental determinants and their interactions
in cancer risk and prevention;
UCCCC SCIENTIFIC REPORT 2010 – 2011
and clinical services to reduce cancer disparities, other health
в– в– Identify the biological and behavioral basis for tobacco
and alcohol use, and apply this knowledge to develop
prevention and cessation-related treatment strategies;
в– в– Examine biological and behavioral factors related to
screening, early detection, and prevention of cancer;
в– в– Investigate the biobehavioral, psychosocial, and
environmental determinants of cancer-related health
outcomes, including survivorship; and
в– в– Examine cost-effectiveness and economic factors related
to cancer diagnosis, treatment, and survivorship.
113
Cancer Prevention and Control
PROGRAM MEMBERSHIP†Habibul Ahsan, MBBS, MMedSc
Professor of Health Studies
Tara Henderson, MD, MPH
Assistant Professor of Pediatrics
Blase Polite, MD, MPH
Assistant Professor of Medicine
Kenneth Alexander, MD, PhD
Professor of Pediatrics
Susan Hong, MD, MPH
Assistant Professor of Medicine
П†Anirban Basu, PhD
Assistant Professor of Medicine
Dezheng Huo, MD, PhD
Assistant Professor of
Health Studies
Iris Romero, MD
Assistant Professor of
Obstetrics/Gynecology
Marc Bissonnette, MD
Associate Professor of Medicine
Eugene Chang, MD
Professor of Medicine
UCCCC SCIENTIFIC REPORT 2010 – 2011 Brian Chiu, PhD
Associate Professor of
Health Studies
Nora Jaskowiak, MD
Assistant Professor of Surgery
П†Lisa Sanchez-Johnsen, PhD
Assistant Professor of Psychiatry
Karen E. Kim, MD, MS
Associate Professor of Medicine
Marion Verp, MD
Associate Professor of
Obstetrics/Gynecology
Andrea King, PhD
Professor of Psychiatry
Rena Conti, PhD
Instructor of Pediatrics
Sonia Kupfer, MD
Assistant Professor of Medicine
Nancy Cox, PhD
Professor of Medicine
Diane Lauderdale, PhD
Associate Professor of
Health Studies
William Dale, MD, PhD
Associate Professor of Medicine
Soma Das, PhD
Associate Professor of
Human Genetics
Harriet de Wit, PhD
Professor of Psychiatry
Anna Di Rienzo, PhD
Professor of Human Genetics
James Dignam, PhD
Associate Professor of
Health Studies
David Grdina, PhD, MBA
Professor of Radiation &
Cellular Oncology
Paul Vezina, PhD
Professor of Psychiatry
Irving Waxman, MD
Professor of Medicine
Yan Chun Li, PhD
Associate Professor of Medicine
Stacy Tessler Lindau, MD, MAPP
Associate Professor of
Obstetrics/Gynecology
Christopher Masi, MD, PhD
Assistant Professor of Medicine
Martha McClintock, PhD
Professor of Psychology
Daniel McGehee, PhD
Associate Professor of Anesthesia/
Critical Care
David Meltzer, MD, PhD
Associate Professor of Medicine
William Green, PhD
Professor of Neurobiology
П†Eneida Mendonca, MD, PhD
Associate Professor of Pediatrics
Yasmin Hasan, MD
Instructor of Radiation &
Cellular Oncology
Olufunmilayo Olopade, MBBS
Professor of Medicine
Joshua Hemmerich, PhD
Assistant Professor of Medicine
David Rubin, MD
Associate Professor of Medicine
Brandon Pierce, PhD
Assistant Professor of
Health Studies
†  Reflects all Program membership during 2010-2011
φ  Individuals who are no longer at the UCCCC
114
Program Highlights††Due to space constraints, only a small representative sample of Program highlights is presented here.
NEURAL SUBSTRATES UNDERLIE
ALCOHOL-INDUCED SMOKING
CHEMOTHERAPEUTIC
DRUG SUSCEPTIBILITYASSOCIATED SNPS ARE
ENRICHED IN EXPRESSION
QUANTITATIVE TRAIT LOCI
(INTERPROGRAMMATIC)
EGFR DOWNREGULATES
TUMOR SUPPRESSORS IN
WESTERN DIET-PROMOTED
COLONIC TUMOR (INTRA/
INTERPROGRAMMTIC)
Previous studies indicate that the
promotion of colonic tumorigenesis requires epidermal growth factor
receptor (EGFR) signaling. Marc
Bissonnette, MD, Sonia Kupfer,
MD, Alessandro Fichera, MD
(Pharmacogenomics and Experimental Therapeutics Program), and
Kathleen Goss, PhD (Molecular
Mechanisms of Cancer Program),
investigated the effects of EGFR
on two micro RNAs (miRNAs),
miR-143 and miR-145. EGFR signals
suppressed the expression of both
miRNAs in murine colonic tumors
and down-regulated their putative
and established targets involved in
cell cycle regulation. The findings
uncover the tumor suppressor role of
miR-143 and miR-145 in the presence
of a Western diet. Approaches that
prevent the down-regulation of these
miRNAs may serve as potential strategies to prevent colon cancer. (Zhu et
al., Mol Cancer Res 9:960-75, 2011)
RACIAL AND ETHNIC
DISPARITIES INFLUENCE RISK
AND SURVIVAL IN CHILDREN
WITH NEUROBLASTOMA
(INTERPROGRAMMATIC)
Tara Henderson, MD, MPH, and
Susan Cohn, MD (Pharmacogenomics and Experimental Therapeutics
Program), evaluated the racial and
ethnic differences in risk factors and
survival in 3,539 pediatric patients
with neuroblastoma enrolled in the
Children’s Oncology Group (COG).
Black and Native American patients
had a higher prevalence of high-risk
disease and 5-year event free survival
(EFS) compared with whites. The
data suggest that this population may
be more resistant to chemotherapy
UCCCC SCIENTIFIC REPORT 2010 – 2011
A strong link exists between cigarette
smoking and alcohol use. Andrea
King, PhD, in a double-blinded,
placebo-controlled, crossover study,
used functional magnetic resonance
imaging to examine the response
to smoking cues in heavy drinking,
nondaily social smokers after
consuming an intoxicating dose of
alcohol or placebo. The consumption
of a moderately intoxicating oral
dose of alcohol increased the desire
to smoke and amplified ventral
striatum reactivity in response to
smoking compared with control
cues. Alcohol also dampened orbitofrontal activity across both cue types,
whereas dorsolateral prefrontal and
anterior cingulate cortex activation
to smoking cues was not affected
by alcohol. These results provide a
potential neurobiological mechanism
to explain the co-abuse of these two
commonly consumed cancer-causing
agents. (King et al., Neuropsychopharmacology 35:692-701, 2010)
for six different anticancer agents.
Chemotherapeutic drug susceptibility-associated SNPs were more likely
to be eQTLs and associated with the
transcriptional expression level of
multiple genes as potential master
regulators. These findings highlight
the importance of genetic variations
in affecting transcript abundance in
elucidating the genetic determinants
of chemotherapeutic drug susceptibility. (Gamazon et al., PNAS
107:9287-92, 2010)
Cancer Prevention and Control
Publications
Pharmacogenomics has employed
both candidate gene studies and
genome-wide association studies
(GWAS) to identify loci associated
with drug response and/or toxicity.
Nancy Cox, PhD, along with M.
Eileen Dolan, PhD, and R. Stephanie
Huang, PhD (Pharmacogenomics
and Experimental Therapeutics
Program), evaluated the genomic
regions and functional categories of
drug susceptibility-associated single
nucleotide polymorphisms (SNPs)
115
Cancer Prevention and Control
UCCCC SCIENTIFIC REPORT 2010 – 2011 and encourage additional studies to
delineate the genetic basis for these
disparities. (Henderson et al., J Clin
Oncol 29:76-82, 2011)
A STRONG CONCORDANCE IN
HORMONE RECEPTOR STATUS
EXISTS BETWEEN PRIMARY AND
SECOND BREAST CANCERS
(INTRAPROGRAMMATIC)
Women with breast cancer are more
susceptible to developing a second
breast cancer than women in the
general population are to developing
a primary breast cancer. Dezheng
Huo, MD, PhD, and Olufunmilayo
Olopade, MBBS, investigated the
histological and biological relationship between primary first and
second breast cancers by analyzing
30,617 patients from the National
Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER)
registries. Strong associations were
found between hormone receptor
status, tumor grade, and histological
type between bilateral breast cancers.
These findings suggest that tumors
arise from a common milieu and
have important implications in the
prevention and management of
second breast cancers. (Huo et al.,
Cancer 117:907-15, 2011)
THE HNF1A REGION IS A
NOVEL PANCREATIC CANCER
SUSCEPTIBILITY LOCUS
SNPs that are associated with human
phenotypes are more likely to associate with pancreatic cancer risk
than SNPs with no known effects.
Brandon Pierce, PhD, and Habibul
Ahsan, MBBS, MMedSc, examined
1,087 SNPs with known implications for human phenotypes for
association with pancreatic cancer
risk. The method increased the
statistical power of the GWA study,
reduced the number of tests conducted, and focused on SNPs with
increased probabilities of disease
risk association. HNF1A, a region
that harbors variants influencing
several human traits, was identified
as a pancreatic cancer-risk locus. This
novel GWA approach may be useful
for identifying susceptibility loci for
other cancer types. (Pierce et al.,
Cancer Res 71:4352-8, 2011)
Grants
STUDY TO IDENTIFY GENETIC
RISK FOR BREAST CANCER IN
THE AFRICAN DIASPORA
Women in the African diaspora suffer
from a disproportionate burden of
pre-menopausal breast cancer in comparison to other races. Olufunmilayo
Olopade, MBBS, was awarded an
R01 grant from the National Cancer
Institute to perform a GWA study
in indigenous African women to
identify alleles associated with breast
cancer risk. Results from this study
have the potential to identify risk
alleles that may have implications for
early detection, prognosis, and treatment of breast cancer in all women.
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Cancer Prevention and Control
Measuring the impact of comorbidities on quality of life (QOL) is an
important factor in treatment selection and evaluation. As a recipient of a
National Cancer Institute R21 award,
William Dale, MD, PhD, is testing
the generalizability of a prediction
model he developed for estimating
QOL in men with prostate cancer
and various comorbidities. Extension of the prediction model will
establish better QOL measurement
for cost-effectiveness analysis for men
at risk for prostate cancer, and may be
applicable in a broader context across
cancer sites and other prevalent noncancer comorbidities.
RESEARCHERS SEARCH FOR
RARE VARIANTS RESPONSIBLE
FOR COMPLEX HUMAN
PHENOTYPES
Nancy Cox, PhD, along with colleagues, was awarded a U01 grant
from the National Human Genome
Research Institute to develop a
program for the analysis of sequence
data from the 1000 Genomes Project.
The program aims to identify rare
variants that affect complex human
traits, determine what proportion
of the heritability for complex traits
is attributable to these variants, and
predict which genes are most likely
to harbor these variants.
PROGRAM AIMS TO DEVELOP
AN ONCOLOGY WORKFORCE
FOR THE 21ST CENTURY
The University of Chicago, under the
leadership of Olufunmilayo Olopade,
MBBS, received the National Cancer
Institute Paul Calabresi Career Development Award for Clinical Oncology
(K12) to create an interdisciplinary
training program in patient-oriented
research for clinicians and basic scientists. The highly mentored, didactic
program provides clinical research
training, enabling participants to
conduct high-quality and highimpact hypothesis-driven bench to
bedside research to make fundamental contributions toward the goal of
personalized cancer treatment.
EGFR-VDR SIGNALS IN DIET
PROMOTE INFLAMMATION
AND CANCER
Diet is thought to play a major role
in the development of sporadic colon
cancer. Marc Bissonnette, MD, has
shown that tumor promotion by
Western-style, high-fat diets requires
the suppression of vitamin D action
by epidermal growth factor receptor
(EGFR) signaling. Through support
from a National Cancer Institute R21
grant, Dr. Bissonnette is uncovering
the EGFR and vitamin D cellular
and molecular pathways that interact
to modulate dietary inflammation
and colonic tumor risk. These studies
will identify potential new targets for
chemoprevention.
UCCCC SCIENTIFIC REPORT 2010 – 2011
PREDICTION MODEL AIDS IN
QOL ASSESSMENT FOR PATIENTS
WITH PROSTATE CANCER
117
Featured Faculty Profiles††Due to space constraints, only a small representative sample of Program members is presented here.
Cancer Prevention and Control
TARA HENDERSON, MD, MPH
Assistant Professor of Pediatrics
Survival after a diagnosis of childhood cancer has improved from less than
20% in the 1960s to over 80% today. As a result, there are over 325,000
childhood cancer survivors in the U.S. Despite these high cure rates, many
survivors are at elevated risk for morbidity as a result of their prior cancer
and its treatment. These risks include the development of second malignant
neoplasms (SMN) and damage to vital organs, which can lead to premature
mortality. Clinicians and researchers must carefully identify those survivors
at risk for SMN and late effects to develop surveillance recommendations
aimed at early detection and treatment.
UCCCC SCIENTIFIC REPORT 2010 – 2011 Tara Henderson, MD, MPH
Dr. Tara Henderson’s research program in childhood cancer survivorship aims
to: 1) identify and describe SMN in childhood cancer survivors, including
treatment-, familial-, and lifestyle-related risk factors associated with their development; 2) develop recommendations for the surveillance and early detection of
SMN; 3) identify barriers and facilitators to survivors receiving appropriate riskbased healthcare including surveillance of SMN; and 4) develop intervention
studies aimed at improving SMN surveillance in childhood cancer survivors.
Dr. Henderson and her colleagues have recently identified 45 cases of gastrointestinal SMN in
the Childhood Cancer Survivor Study, a cohort of over 14,000 childhood cancer survivors diagnosed between 1970 and 1986. This risk is almost 5-fold higher than the general population. Risk
of the development of these tumors was associated with prior diagnosis of Hodgkin lymphoma
or Wilms tumor, as well as exposure to abdominal radiation, platinum chemotherapy, and highdose procarbazine.
In addition, Dr. Henderson and her collaborators performed large studies of subspecialists and
primary care physicians to determine their attitudes regarding this population and their knowledge of late effects and available surveillance guidelines.1 Pediatric oncologists described being
uncomfortable with older survivors, and many were unaware of the available screening guidelines,
such as those for women at high risk for breast cancer. Dr. Henderson recently completed a study
of 1500 U.S. family physicians, which was reported at the 2011 American Society of Clinical
Oncology meeting. Similarly, the study found that while these physicians are willing to care for
survivors, most are not aware of the available surveillance guidelines for these patients.
1 Henderson TO, Hlubocky FJ, Wroblewski KE, Diller L, Daugherty CK. Physician preferences and knowledge gaps regarding the care
of childhood cancer survivors: a mailed survey of pediatric oncologists. J Clin Oncol 28:878-883, 2010.
118
Assistant Professor of Health Studies
Dr. Dezheng Huo focuses his research on the genetic and molecular epidemiology of breast cancer with an emphasis on health disparity and global health.
He has published extensively on cancer epidemiology and utilizes a population approach to understand the molecular subtypes of breast cancer. The
breadth of his research interest is reflected in his multiple research projects,
including a validation and fine-mapping study of breast cancer susceptibility
loci in women of African ancestry; a two-country case-control study of breast
cancer subtypes; reproductive and lifestyle factors that influence breast cancer
in African populations; a genome-wide association study of breast cancer in
women of African ancestry; a molecular epidemiological study of microRNAs
as biomarkers for breast cancer; a systemic study of treatment utilization and
health disparity using national databases; and a study of hormone receptor
concordance among primary breast cancers.
Dr. Huo also conducts research on prostate cancer. For example, he and his colleagues have
analyzed data from the National Health Interview Survey to examine PSA screening rates as a
function of age, life expectancy, and other factors. Excessive PSA screening was documented in
elderly men with limited life expectancies, which may lead to unnecessary anxiety, diagnoses,
treatment, and healthcare expenditures without meaningful clinical benefit.3
UCCCC SCIENTIFIC REPORT 2010 – 2011
Recently, Dr. Huo’s group used the Surveillance Epidemiology and End
Dezheng Huo, MD, PhD
Results (SEER) database to examine the hormone receptor status of 30,617
patients diagnosed with bilateral breast cancers between 1990 and 2007. A
strong agreement was found between estrogen receptor status and having two bilateral tumors
even in cases separated by 10 years or longer, suggesting that two tumors arise in a common
milieu, and tumor subtypes are predetermined in the early stage of breast carcinogenesis.1 Using
sequencing technique, Dr. Huo and colleagues showed that germline mutations of the MERIT40
gene are not responsible for the elevated risk of breast cancer associated with this genomic locus,
suggesting regulatory variation might be important for common diseases like breast cancer.2
Cancer Prevention and Control
DEZHENG HUO, MD, PHD
1 Huo D, Melkonian S, Rathouz P, Khramtsov A, Olopade OI. Concordance in histological and biological parameters between first
and second primary breast cancers. Cancer 117:907-915, 2011.
2 Zheng Y, Zhang J, Niu Q, Olopade OI, Huo D. Germline mutational analysis of the C19orf62 gene in African-American women
with breast cancer. Breast Cancer Res Treat 127:871-877, 2011.
Drazer MW, Huo D, Schonberg MA, Razmaria A, Eggener SE. Population-based patterns and predictors of PSA screening among
older men in the United States. J Clin Oncol 29:1736-1743, 2011.
3
119
UCCCC SCIENTIFIC REPORT 2010 – 2011 Cancer Prevention and Control
BRANDON PIERCE, PHD
Assistant Professor of Health Studies
Dr. Pierce is an epidemiologist working in the context of large cohort and
case-control studies of cancer. His research focuses on the interrelated roles
of genetic, molecular, and environmental factors in cancer risk and prognosis
with an emphasis on breast, prostate, and pancreatic cancer. Dr. Pierce’s laboratory uses high-dimensional genomic data, such as genome-wide genotype
data and DNA methylation data, to identify cancer risk and prognostic factors
and also to elucidate cancer-related biological mechanisms. He is interested
in developing and employing innovative methods for identifying cancerassociated genes and gene-environment interactions, and in using genetic data
for causal inference in the epidemiological setting. The environmental factors
of interest to Dr. Pierce include arsenic and diabetes mellitus.
Dr. Pierce’s various research projects are focused on 1) using novel methods
to identify cancer susceptibility genes from genome-wide association data;
2) identifying cancer-related methylation features in multiethnic studies
Brandon Pierce, PhD
of human prostate tissue; 3) developing and implementing “Mendelian
randomization” methods to assess the causality of cancer risk factors in epidemiological studies; and 4) assessing the effect of arsenic, a known carcinogen, on genomic features
such as telomeres.
In recent work, Dr. Pierce used a “pleiotropy scan” approach to identify HNF1A as a pancreatic cancer susceptibility gene.1 A large genome-wide association study of pancreatic cancer was
restricted to genetic variants that have been reported to associate with human phenotypes in prior
genome-wide association studies. This approach provided enhanced power to detect associations,
resulting in the identification of a novel pancreatic cancer susceptibility factor. In another recent
study, Dr. Pierce and colleagues discovered that susceptibility to arsenic toxicity varies substantially
by the type of diet consumed.2 Using data from a large longitudinal study of arsenic exposure in
Bangladesh, they identified three distinct types of diets and found that among individuals with
high intakes of gourds and root vegetables, there was a substantially lower risk for developing
arsenical skin lesions and a weaker effect of arsenic on skin lesion risk. Such information will have
implications for future efforts to prevent arsenic toxicity in Bangladesh.
1 Pierce BL and Ahsan H. Genome-wide “pleiotropy scan” identifies HNF1A region as a novel pancreatic cancer susceptibility locus.
Cancer Res 71:4352-4358, 2011.
2
Pierce BL, Argos M, Chen Y, et al. Arsenic exposure, dietary patterns, and skin lesion risk in Bangladesh: A prospective study. Am
J Epidemiol 173:345-354, 2011.
120
Cancer Prevention and Control
SONIA KUPFER, MD
Assistant Professor of Medicine
Dr. Sonia Kupfer is a physician scientist in the Section of Gastroenterology
with a translational research laboratory as well as a clinical practice. She is in
the first year of her NIH K08 career development grant, and her broad area
of interest is in colorectal cancer prevention with a specific focus on highrisk populations. Colorectal cancer is one of the three most common causes
of cancer and cancer deaths, with African Americans having the highest
colorectal cancer incidence and mortality of all U.S. populations. Fortunately,
with high-quality screening and removal of pre-cancerous polyps, colorectal
cancer is a preventable cancer. One focus of Dr. Kupfer’s clinical practice is in
testing and treating individuals with hereditary colorectal cancer syndromes,
such as Lynch syndrome and familial adenomatous polyposis (FAP). While
genetic testing is available for these patients to help identify those at risk,
genetic and environmental factors that put the general population at risk
for colorectal cancer are incompletely understood and form the basis of her
research program.
Sonia Kupfer, MD
In a recent study, Dr. Kupfer and her colleagues reported the results of a genome-wide study
of genetic variants in colorectal cancer patients.1 They sought to replicate 22 single nucleotide
polymorphism associations in a large African American case-control series and found heterogeneity in the results. These findings, which are informing our ongoing fine-mapping studies, suggest
that different markers may be associated in a non-European population. A second recent study of
vitamin D receptor (VDR) gene polymorphism associations did not show significant associations
between VDR genetic variants and colorectal cancer. Preliminary evidence for a possible geneenvironment interaction was found, but requires validation in a larger sample.
UCCCC SCIENTIFIC REPORT 2010 – 2011
Dr. Kupfer’s goal is to identify genetic susceptibility factors for colorectal
cancer using complementary approaches including genome-wide, candidate gene, and gene
expression studies. A large, racially diverse case-control series has been assembled in collaboration
with the University of North Carolina and the University of Illinois at Chicago. The first aim is
to fine-map colorectal cancer genetic variants discovered using genome-wide association studies.
Dr. Kupfer and her collaborators are utilizing next-generation sequencing to identify novel and
functional variants in these regions. Her second aim is to investigate genetic and environmental
factors in vitamin D metabolism in relation to colorectal cancer. Vitamin D is a protective factor
against colorectal cancer and is an excellent candidate for chemoprevention. The third aim of Dr.
Kupfer’s laboratory is to perform expression quantitative loci mapping in the healthy and diseased
human gastrointestinal tract.
1 Kupfer SS, Anderson JR, Hooker S, Skol A, Kittles RA, Keku TO, Sandler RS, Ellis NA. Genetic heterogeneity in colorectal cancer
associations between African and European americans. Gastroenterology 139:1677-1685, 2010.
121
Cancer Prevention and Control
STACY TESSLER LINDAU, MD, MAPP
Associate Professor of Obstetrics/Gynecology
Dr. Stacy Lindau is a population- and clinic-based researcher with expertise
in female aging and sexuality at the interface of cancer and other complex
illnesses. She has helped pioneer the biosocial survey research field, incorporating cutting-edge, minimally invasive methods for obtaining biological
and physiological data in population-based research. She created and directs
the National Institute on Aging (NIA)-funded Chicago Core on Biomeasures in Population-Based Aging Research at the Center on Demography
and Economics of Aging, a complementary clinical core at The University of
Chicago Institute for Translational Medicine, and the Program in Integrative
Sexual Medicine (PRISM) for Women and Girls with Cancer. In addition,
Dr. Lindau’s laboratory focuses on urban health. She directs the South Side
Health and Vitality Studies of the Urban Health Initiative, which focus on
how technology assets can be optimized to promote health in low-income
urban communities.
UCCCC SCIENTIFIC REPORT 2010 – 2011 Stacy Tessler Lindau, MD, MAPP
PRISM provides comprehensive clinical care for women seeking treatment and
prevention for sexual problems and to recover sexual function following cancer
treatment. Since its inception in October 2008, the clinic has seen 117 unique patients, 75 of whom
have cancer. Its multidisciplinary design includes collaborations with gynecology oncology, radiation
oncology, certified sex therapy, pelvic physical therapy, dermatology and other relevant specialties. A
needs assessment carried out by Dr. Lindau and colleagues demonstrated that nearly half of the 261
gynecologic and breast cancer patients surveyed reported sexual concerns, yet only 7% had recently
sought medical care for these concerns.1
PRISM’s prospective, longitudinal patient registry tracks the prevalence, evolution, and treatment
outcomes in PRISM patients. The registry serves as a foundation for multisite collaboration to
accelerate research and improve sexual outcomes for females with cancer. Fifty-six patients have
been enrolled. An abstract documenting this unique registry was presented in June 2011 at the
Cancer Survivors and Sexual Health Symposium, held by the International Society for Sexual
Medicine, in Washington, DC.2
To create an infrastructure to support multisite research, interdisciplinary teams from the UCCCC
and Memorial Sloan-Kettering Cancer Center jointly developed the mission for a national conference to convene active clinicians and researchers in the field of cancer and female sexuality. In
November 2010, 43 researchers from 20 institutions across 14 states attended the 1st National
Conference on Cancer and Female Sexuality in Chicago, IL. Scientific working groups were
established to help promote research in this field. An abstract documenting this work was also
recently presented at the Cancer Survivors and Sexual Health Symposium in Washington, DC.
1 Hill EK, Sandbo S, Abramsohn E, Makelarski J, Wroblewski K, Wenrich ER, McCoy S, Temkin SM, Yamada SD, Lindau ST.
Assessing gynecologic and breast cancer survivors’ sexual health care needs. Cancer 117:2643-2651, 2010.
2 Abramsohn EM, Makelarski J, Baron SL, Florendo J, Githens K, Sandbo S, Sobecki J, Yamada SD, Lindau ST. Foundation for a
multi-site registry to accelerate research and improve sexual outcomes for females with cancer. Presented at: Cancer Survivorship and
Sexual Health Symposium, Washington DC, 2011.
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Cancer Prevention and Control
DANIEL MCGEHEE, PHD
Associate Professor of Anesthesia/Critical Care
Dr. Daniel McGehee’s laboratory is investigating the cellular mechanisms
underlying nicotine addiction – one of the most common causes of cancer
in this country. His work has centered on studying the impact of nicotinic
receptor activation on the output of the midbrain dopamine system, which is
a central component of the brain’s reward circuitry. Dr. McGehee’s research
has shown that in addition to the direct excitation of dopamine neurons that
occurs via nicotinic receptor activation, these receptors also activate changes
in synaptic drive to these cells. One critically important synaptic change is
long-term potentiation (LTP) of the excitatory inputs to midbrain dopamine
neurons. Increased dopamine activity is necessary for the rewarding effects
of nicotine, and both of these effects are blocked when animals are treated
with drugs that inhibit LTP induction. Therefore, his laboratory has focused
on understanding the mechanisms that link nicotine exposure to LTP of the
excitatory inputs to midbrain dopamine neurons.
Daniel McGehee, PhD
The co-abuse of ethanol and tobacco products increases the prevalence of abuse of both these
drugs. Current investigations are testing the interaction of ethanol with nicotinic receptors
in brain reward and motor control circuitry. The results indicate remarkable modifications in
nicotinic receptor function that are mediated by changes in the adenylyl cyclase/cAMP/protein
kinase A system. The interactions of these two drugs at nicotinic receptors may contribute to the
behavioral consequences of co-abuse of nicotine and ethanol.
UCCCC SCIENTIFIC REPORT 2010 – 2011
Recently, the McGehee laboratory used an in vitro exposure paradigm to
study the effect of nicotine on excitatory synaptic strength. Brief exposure of
nicotine to brain slices from drug-naive adult rats followed by a period of recovery resulted in an
NMDA glutamate receptor (NMDAR)-dependent increase in the strength of excitatory inputs to
midbrain dopamine neurons.1 The induction of synaptic potentiation required direct excitation
via nicotinic receptors on dopamine neurons, as well as an enhancement of NMDAR function via
D5 dopamine receptors, also on DA neurons. Nicotine-induced increase of presynaptic glutamate
release also contributed to the induction of synaptic plasticity. These results identified important
receptor systems involved in nicotine-induced long-term changes in excitatory synaptic input to
midbrain dopamine neurons. The data also revealed remarkable similarity in the mechanisms
underlying synaptic plasticity induced by nicotine and cocaine in the VTA.
1 Mao D, Gallagher K, McGehee DS. Nicotine potentiation of excitatory inputs to ventral tegmental area dopamine neurons.
J Neurosci 31:6710-6720, 2011.
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Cancer Prevention and Control
ANDREA KING, PHD
Professor of Psychiatry
Dr. Andrea King’s research projects include integrated human laboratory and
clinical trials research methodology to bear a psychobiological perspective on
addiction. The primary goal of her research is to examine the mechanisms of
vulnerability to substance use disorders and to identify efficacious behavioral
and pharmacological interventions for treatment of addiction, particularly
alcohol and nicotine dependence. Dr. King is also involved in research to
identify and ultimately reduce health disparities for these disorders among
racial/ethnic minorities and women. Human laboratory methodologies
have been used to determine acute subjective, objective, and performance
effects of alcohol in high- and low-risk drinkers and to examine how alcohol
affects smoking urges and behaviors. Clinical and prospective studies in the
laboratory are used to study innovative pharmacological and behavioral interventions for alcohol and tobacco use disorders and track changes in substance
use patterns over time.
UCCCC SCIENTIFIC REPORT 2010 – 2011 Andrea King, PhD
Recent work in Dr. King’s laboratory has shown that heavy social “binge”
drinkers are more sensitive to positive-like hedonic and motivational effects of
alcohol than light drinkers, and that this response pattern is predictive of future alcohol problems.1
These results challenge conventional theories that vulnerability to alcohol use disorders is the
result of a low-level response to alcohol. Dr. King’s group has been the first to conduct large-scale
rigorous laboratory tests with intensive follow-up scale to shift the paradigm to newer models
of addiction propensity.2 They have also identified potentially important protective mechanisms
garnering some individuals at low risk for future alcohol problems. Additionally, other recent work
in the King laboratory has examined behavioral and neurobiological mechanisms underlying alcohol’s elicitation of smoking urge and behavior. Recent research in the laboratory using functional
magnetic resonance imaging (fMRI) has shown that the brain region related to addiction processes (ventral striatum) is activated by alcohol during viewing of salient smoking vs. non-smoking
images.3 Current investigations are under way to examine interventions and longer-term course of
alcohol and smoking behaviors.
1 King AC, de Wit H, McNamara PJ, Cao D. Rewarding, stimulant and sedative alcohol responses and relationship to future binge
drinking. Arch Gen Psychiatry 68:389-399, 2011.
2 King AC, Roche DJO, Rueger SY. Subjective responses to alcohol: A paradigm shift may be brewing. Alcohol Clin Exp Res 35:17261728, 2011.
3 King AC, McNamara PJ, Angstadt M, Phan KL. Neural substrates of alcohol-induced smoking urge in heavy drinking nondaily
smokers. Neuropsychopharmacology 35:692-701, 2010.
124
Associate Professor of Medicine
Dr. Karen Kim’s research interests are focused on understanding the impact of
culturally appropriate and linguistically specific primary and secondary cancer
prevention among minority populations with a specific focus on colorectal
and hepatitis B-induced liver cancer. Her primary interest is to understand the
role of collaborative community partnerships in improving population-level
health outcomes by creating sustainable environmental changes in minority
community sectors in which health-related behaviors occur. Specifically,
Dr. Kim’s research team utilizes a multi-sector approach as a mechanism for
information sharing, coordination, and bidirectional evaluation of processes
of care models to enhance cancer screening and prevention.
Recently, Dr. Kim’s group has been the recipient of a Centers for Disease Control and Prevention
conference grant to host a Midwest Viral Hepatitis Conference to address these barriers. Dr. Kim’s
research should serve as a framework for healthcare policies that will enhance access and reduce
cancer disparities among underserved populations.
UCCCC SCIENTIFIC REPORT 2010 – 2011
In collaboration with the non-profit organization, Asian Health Coalition,
Dr. Kim developed the Hepatitis Education and Prevention Program as a
multi-tiered dissemination model, integrating bilingual community health
workers, academic institutions, and public health systems to study the impact
Karen E. Kim, MD, MS
of interventions on hepatitis B-related outcomes and to serve as a platform for
policy and advocacy for underserved Asian Americans. This work has resulted
in three interesting observations: 1) the absence of bilingual health systems for monolingual
Asians is a significant barrier to care; 2) stigma associated with hepatitis B, especially among Asian
immigrants, inhibits adequate integration into care; and 3) the paucity of knowledge about hepatitis B risk stratification among the health system significantly contributes to the early morbidity
and mortality from the disease among Asian Americans.
Cancer Prevention and Control
KAREN E. KIM, MD, MS
125
Selected Publications
UCCCC SCIENTIFIC REPORT 2010 – 2011 Cancer Prevention and Control
* : Intraprogrammatic Collaboration
# : Interprogrammatic Collaboration
AHSAN, HABIBUL,
MBBS, MMEDSC
* Pierce BL, Ahsan H, Vanderweele TJ.
Power and instrument strength requirements for Mendelian randomization
studies using multiple genetic variants.
Int J Epidemiol 40:740-52, 2011.
PMC3147064
* Argos M, Kalra T, Rathouz PJ, Chen
Y, Pierce B, Parvez F, Islam T, Ahmed
A, Rakibuz-Zaman M, Hasan R,
Sarwar G, Slavkovich V, van Geen A,
Graziano J, Ahsan H. Arsenic exposure
from drinking water, and all-cause and
chronic-disease mortalities in Bangladesh
(HEALS): a prospective cohort study.
Lancet 376:252-8, 2010.
* Pierce BL, Ahsan H. Genetic susceptibility to type 2 diabetes is associated with
reduced prostate cancer risk. Hum Hered
69:193-201, 2010. PMC2866577
* Argos M, Kalra T, Pierce BL, Chen Y,
Parvez F, Islam T, Ahmed A, Hasan R,
Hasan K, Sarwar G, Levy D, Slavkovich
V, Graziano JH, Rathouz PJ, Ahsan H.
A prospective study of arsenic exposure
from drinking water and incidence of skin
lesions in Bangladesh. Am J Epidemiol
174:185-94, 2011.
* Pierce BL, Ahsan H. Genome-wide
“pleiotropy scan” identifies HNF1A region
as a novel pancreatic cancer susceptibility locus. Cancer Res 71:4352-8, 2011.
PMC3129443
* Pierce BL, Austin MA, Ahsan H. Association study of type 2 diabetes genetic
susceptibility variants and risk of pancreatic cancer: an analysis of PanScan-I data.
Cancer Causes Control 22:877-83, 2011.
* Pierce BL, Argos M, Chen Y, Melkonian
S, Parvez F, Islam T, Ahmed A, Hasan R,
Rathouz PJ, Ahsan H. Arsenic exposure,
dietary patterns, and skin lesion risk in
bangladesh: a prospective study. Am J Epidemiol 173:345-54, 2011. PMC3105269
* Melkonian S, Argos M, Pierce BL,
Chen Y, Islam T, Ahmed A, Syed EH,
Parvez F, Graziano J, Rathouz PJ, Ahsan
H. A prospective study of the synergistic
effects of arsenic exposure and smoking,
sun exposure, fertilizer use, and pesticide
126
use on risk of premalignant skin lesions
in Bangladeshi men. Am J Epidemiol
173:183-91, 2011. PMC3011951
BASU, ANIRBAN, PHD
* Basu A, Dale W, Elstein A, Meltzer D. A
time tradeoff method for eliciting partner’s
quality of life due to patient’s health states
in prostate cancer. Med Decis Making
30:355-65, 2010.
* Meltzer D, Basu A, Conti R. The
economics of comparative effectiveness
studies: societal and private perspectives
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LI, YAN CHUN, PHD
Zhang Y, Kong J, Deb DK, Chang A, Li
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Arch Biochem Biophys 507:241-7, 2011.
PMC3049452
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LINDAU, STACY TESSLER, MD,
MAPP
Lindau ST, Surawska H, Paice J, Baron
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# Hill EK, Sandbo S, Abramsohn E,
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McCoy S, Temkin SM, Yamada SD, Lindau
ST. Assessing gynecologic and breast cancer
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MASI, CHRISTOPHER, MD, PHD
Masi CM, Hawkley LC, Cacioppo JT.
Serum 2-methoxyestradiol, an estrogen
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Patel S, Hawkley LC, Cacioppo JT,
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MCCLINTOCK, MARTHA, PHD
* # Gehlert S, Murray A, Sohmer D,
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O. The importance of transdisciplinary
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Vilhauer RP, McClintock MK, Matthews
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MCGEHEE, DANIEL, PHD
* Chang B, Daniele CA, Gallagher K,
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raphe to the nucleus accumbens. J Neurophysiol 106:801-8, 2011. PMC3154831
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PMC3118498
MELTZER, DAVID, MD, PHD
Meltzer D. Cost-effectiveness analysis
in oncology. Clin Adv Hematol Oncol
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* Dale W, Bilir SP, Hemmerich J, Basu A,
Elstein A, Meltzer D. The prevalence, correlates, and impact of logically inconsistent
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Meltzer DO, Detsky AS. The real meaning
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Helfand M, Tunis S, Whitlock EP, Pauker
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Kent DM. A CTSA agenda to advance
methods for comparative effectiveness
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* Meltzer D, Basu A, Conti R. The
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* Basu A, Dale W, Elstein A, Meltzer D. A
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MENDONCA, ENEIDA, MD, PHD
# Surati M, Robinson M, Nandi S, Faoro
L, Demchuk C, Rolle CE, Kanteti R,
Ferguson BD, Hasina R, Gangadhar
TC, Salama AK, Arif Q, Kirchner C,
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* Ogundiran TO, Huo D, Adenipekun
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Adebamowo C, Olopade OI. Case-control
study of body size and breast cancer risk
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172:682-90, 2010. PMC2950817
* # Cohen EE, Haraf DJ, Kunnavakkam
R, Stenson KM, Blair EA, Brockstein B,
Lester EP, Salama JK, Dekker A, Williams
R, Witt ME, Grushko TA, Dignam
JJ, Lingen MW, Olopade OI, Vokes
EE. Epidermal growth factor receptor
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PMC2903330
* Sun C, Huo D, Southard C, Nemesure
B, Hennis A, Cristina Leske M, Wu SY,
Witonsky DB, Olopade OI, Di Rienzo A.
A signature of balancing selection in the
region upstream to the human UGT2B4
gene and implications for breast cancer
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* Zheng Y, Zhang J, Niu Q, Olopade OI,
Huo D. Germline mutational analysis of
the C19orf62 gene in African-American
women with breast cancer. Breast Cancer
Res Treat 127:871-7, 2011.
* Sun C, Huo D, Nemesure B, Hennis
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Q, Olopade OI, Rienzo AD. Lack of
association between common UGT2B
nonsynonymous SNPs and breast cancer
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# Best T, Li D, Skol AD, Kirchhoff T,
Jackson SA, Yasui Y, Bhatia S, Strong LC,
Domchek SM, Nathanson KL, Olopade
OI, Huang RS, Mack TM, Conti DV,
Offit K, Cozen W, Robison LL, Onel K.
Variants at 6q21 implicate PRDM1 in
the etiology of therapy-induced second
malignancies after Hodgkin’s lymphoma.
Nat Med 17:941-3, 2011.
* Campbell MJ, Tonlaar NY, Garwood
ER, Huo D, Moore DH, Khramtsov AI,
Au A, Baehner F, Chen Y, Malaka DO,
Lin A, Adeyanju OO, Li S, Gong C,
McGrath M, Olopade OI, Esserman LJ.
Proliferating macrophages associated with
high grade, hormone receptor negative
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Breast Cancer Res Treat 128:703-11, 2011.
El Dinali M, Hasina R, Bragelmann J,
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Bang YJ, Kim WH, Tretiakova M, Vokes
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R. RON (MST1R) is a novel prognostic
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PIERCE, BRANDON, PHD
* Pierce BL, Austin MA, Ahsan H. Association study of type 2 diabetes genetic
susceptibility variants and risk of pancreatic cancer: an analysis of PanScan-I data.
Cancer Causes Control 22:877-83, 2011.
* Argos M, Kalra T, Pierce BL, Chen Y,
Parvez F, Islam T, Ahmed A, Hasan R,
Hasan K, Sarwar G, Levy D, Slavkovich
V, Graziano JH, Rathouz PJ, Ahsan H.
A prospective study of arsenic exposure
from drinking water and incidence of skin
lesions in Bangladesh. Am J Epidemiol
174:185-94, 2011.
* Pierce BL, Ahsan H. Genome-wide
“pleiotropy scan” identifies HNF1A region
as a novel pancreatic cancer susceptibility locus. Cancer Res 71:4352-8, 2011.
PMC3129443
* Pierce BL, Argos M, Chen Y, Melkonian
S, Parvez F, Islam T, Ahmed A, Hasan R,
Rathouz PJ, Ahsan H. Arsenic exposure,
dietary patterns, and skin lesion risk in
bangladesh: a prospective study. Am J Epidemiol 173:345-54, 2011. PMC3105269
* Melkonian S, Argos M, Pierce BL,
Chen Y, Islam T, Ahmed A, Syed EH,
Parvez F, Graziano J, Rathouz PJ, Ahsan
H. A prospective study of the synergistic
effects of arsenic exposure and smoking,
sun exposure, fertilizer use, and pesticide
use on risk of premalignant skin lesions
in Bangladeshi men. Am J Epidemiol
173:183-91, 2011. PMC3011951
UCCCC SCIENTIFIC REPORT 2010 – 2011
* Shah LM, King AC, Basu A, Krishnan
JA, Borden WB, Meltzer D, Arora V.
Effect of clinician advice and patient
preparedness to quit on subsequent quit
attempts in hospitalized smokers. J Hosp
Med 5:26-32, 2010.
OLOPADE, OLUFUNMILAYO,
MBBS
Cancer Prevention and Control
Meltzer DO, Hoomans T, Chung JW, Basu
A. Minimal modeling approaches to value
of information analysis for health research.
Med Decis Making 31:E1-22, 2011.
* Argos M, Kalra T, Rathouz PJ, Chen
Y, Pierce B, Parvez F, Islam T, Ahmed A,
Rakibuz-Zaman M, Hasan R, Sarwar G,
Slavkovich V, van Geen A, Graziano J,
Ahsan H. Arsenic exposure from drinking
water, and all-cause and chronic-disease
mortalities in Bangladesh (HEALS):
a prospective cohort study. Lancet
376:252-8, 2010.
# Catenacci DV, Cervantes G, Yala S,
Nelson EA, El-Hashani E, Kanteti R,
131
Cancer Prevention and Control
UCCCC SCIENTIFIC REPORT 2010 – 2011 * Pierce BL, Ahsan H, Vanderweele TJ.
Power and instrument strength requirements for Mendelian randomization
studies using multiple genetic variants.
Int J Epidemiol 40:740-52, 2011.
PMC3147064
* Pierce BL, Ahsan H. Genetic susceptibility to type 2 diabetes is associated with
reduced prostate cancer risk. Hum Hered
69:193-201, 2010. PMC2866577
POLITE, BLASE, MD, MPH
# Sharma MR, Wroblewski, MPH K,
Polite BN, Knost JA, Wallace JA, Modi S,
Sleckman BG, Taber D, Vokes EE, Stadler
WM, Kindler HL. Dasatinib in previously
treated metastatic colorectal cancer: a
phase II trial of the University of Chicago
Phase II Consortium. Invest New Drugs,
2011 (Epub ahead of print).
Moy B, Polite BN, Halpern MT, Stranne
SK, Winer EP, Wollins DS, Newman LA.
American Society of Clinical Oncology
policy statement: Opportunities in the
Patient Protection and Affordable Care
Act to reduce cancer care disparities. J
Clin Oncol 29:3816-24, 2011.
Polite BN, Sing A, Sargent DJ, Grothey
A, Berlin J, Kozloff M, Feng S. Exploring
racial differences in outcome and treatment for metastatic colorectal cancer:
Results from a large prospective observational cohort study (BRiTE). Cancer,
2011 (Epub ahead of print).
de Souza JA, Polite BN, Manning WG,
Fendrick AM, Ratain MJ. Value-based
insurance design in oncology. Lancet
Oncol 12:321-3, 2011.
Catenacci DV, Kozloff M, Kindler HL,
Polite B. Personalized colon cancer care
in 2010. Semin Oncol 38:284-308, 2011.
PMC3065981
# Ocean AJ, Polite B, Christos P, Horvath
L, Hamilton A, Matulich D, Chen HX,
Sparano JA, Kindler HL. Cetuximab
is associated with excessive toxicity
when combined with bevacizumab Plus
mFOLFOX6 in metastatic colorectal
carcinoma. Clin Colorectal Cancer
9:290-6, 2010.
# Mell LK, Jeong JH, Nichols MA, Polite
BN, Weichselbaum RR, Chmura SJ.
Predictors of competing mortality in early
breast cancer. Cancer 116:5365-73, 2010.
* # Mell LK, Dignam JJ, Salama JK,
Cohen EE, Polite BN, Dandekar V, Bhate
132
AD, Witt ME, Haraf DJ, Mittal BB,
Vokes EE, Weichselbaum RR. Predictors of competing mortality in advanced
head and neck cancer. J Clin Oncol
28:15-20, 2010.
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72:1052-6, 2010.
ROMERO, IRIS, MD
Konda VJ, Chennat JS, Hart J, Waxman I.
Confocal laser endomicroscopy: potential
in the management of Barrett’s esophagus.
Dis Esophagus 23:E21-31, 2010.
# Chen L, Park SM, Tumanov AV, Hau
A, Sawada K, Feig C, Turner JR, Fu
YX, Romero IL, Lengyel E, Peter ME.
CD95 promotes tumour growth. Nature
465:492-6, 2010. PMC2879093
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72:632-6, 2010.
# Zillhardt M, Park SM, Romero
IL, Sawada K, Montag A, Krausz T,
Yamada SD, Peter ME, Lengyel E.
Foretinib (GSK1363089), an orally
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Kahi CJ, Anderson JC, Waxman I,
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High-definition chromocolonoscopy vs.
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for average-risk colorectal cancer screening. Am J Gastroenterol 105:1301-7, 2010.
RUBIN, DAVID, MD
* # Pekow JR, Dougherty U, Mustafi R,
Zhu H, Kocherginsky M, Rubin DT,
Hanauer SB, Hart J, Chang EB, Fichera
A, Joseph LJ, Bissonnette M. miR-143 and
miR-145 are downregulated in ulcerative
colitis: Putative regulators of inflammation and protooncogenes. Inflamm Bowel
Dis, 2011 (Epub ahead of print).
* # Pekow JR, Hetzel JT, Rothe JA,
Hanauer SB, Turner JR, Hart J, Noffsinger
A, Huo D, Rubin DT. Outcome after
surveillance of low-grade and indefinite
dysplasia in patients with ulcerative colitis.
Inflamm Bowel Dis 16:1352-6, 2010.
PMC3046461
VEZINA, PAUL, PHD
* Chang B, Daniele CA, Gallagher K,
Madonia M, Mitchum RD, Barrett L,
Vezina P, McGehee DS. Nicotinic excitation of serotonergic projections from dorsal
raphe to the nucleus accumbens. J Neurophysiol 106:801-8, 2011. PMC3154831
WAXMAN, IRVING, MD
Waxman I, Chennat J, Konda V. Peroral
direct cholangioscopic-guided selective
intrahepatic duct stent placement with an
ultraslim endoscope. Gastrointest Endosc
71:875-8, 2010.
Waxman I, Dillon T, Chmura K, Wardrip
C, Chennat J, Konda V. Feasibility of
a novel system for intraductal balloonanchored direct peroral cholangioscopy
and endotherapy with an ultraslim endo-
* # Chennat J, Konda VJ, MadrigalHoyos E, Fernandez-Sordo J, Xiao SY,
Hart J, Waxman I. Biliary confocal laser
endomicroscopy real-time detection of
cholangiocarcinoma. Dig Dis Sci, 2011
(Epub ahead of print).
Selected Major Grants and Awards
INVESTIGATOR
TITLE
PROJECT
START
DATE
END DATE
TOTAL
ANNUAL
COST
CLASS
9/30/2010
7/31/2015
$2,000,000
R01
National Cancer
Institute
FUNDING AGENCY
Chemoprevention of arsenic-induced skin
cancer
HABIBUL AHSAN
A genome-wide investigation of
autozygosity and breast cancer risk
7/1/2010
7/31/2012
$156,000
N/A
Department of
Defense
MARC
BISSONNETTE
EGFR-VDR signals in diet promoted
inflammation and cancer
3/1/2010
2/29/2012
$197,473
R21
National Cancer
Institute
EUGENE CHANG
IBD and mucosal inflammation,
immunology, and microbiology of the GI
tract
2/25/2011
11/30/2015
$1,100,000
P30
National Institutes
of Health
EUGENE CHANG
The role of enteric microbiota in mediating
the bioavailability and actions of
daikenchuto
1/1/2011
12/31/2011
$268,689
N/A
TSUMURA USA
INC.
NANCY COX
Rare variants and complex human
phenotypes
7/1/2010
3/31/2012
$448,329
U01
National Institutes
of Health
NANCY COX
Using the transcriptome for SNP and gene
annotation
9/17/2010
7/31/2012
$321,012
R01
National Institute
on Mental Health
WILLIAM DALE
Utility-assessment for co-morbidities in
prostate cancer
7/2/2010
7/1/2011
$168,861
R21
National Cancer
Institute
WILLIAM DALE
John A. Hartford Foundation's Center of
Excellence National Program Award
7/1/2011
6/30/2012
$120,000
N/A
American
Federation for
Aging Research
WILLIAM GREEN
The neuronal alpha-bungarotoxin binding
site
8/1/2010
7/31/2011
$342,309
R01
National Institute
of Neurological
Disorders and
Stroke
SONIA KUPFER
Genetic association studies in African
American colorectal cancer patients
9/17/2010
8/31/2015
$164,376
K08
National Cancer
Institute
DAVID MELTZER
UC/UIC Comparative Effectiveness
Research Institutional Career Development
Award
9/30/2010
9/29/2013
$811,907
KM1
National Cancer
Institute
OLUFUNMILAYO
OLOPADE
Developing a global oncology workforce
for the 21st century
8/12/2010
7/31/2015
$571,564
K12
National Institutes
of Health
OLUFUNMILAYO
OLOPADE
Genome-wide association study of breast
cancer in the African Diaspora
8/1/2010
7/31/2013
$419,055
R01
National Cancer
Institute
OLUFUNMILAYO
OLOPADE
Developing an infrastructure to conduct
clinical breast cancer trials in resource
poor nations such as Nigeria
10/1/2010
9/30/2011
$223,000
N/A
Breast Cancer
Research
Foundation
OLUFUNMILAYO
OLOPADE
Targeting the Fanconi anemia-BRCA1
pathway to breast cancer
10/1/2010
9/30/2011
$223,000
N/A
Breast Cancer
Research
Foundation
UCCCC SCIENTIFIC REPORT 2010 – 2011
HABIBUL AHSAN
Cancer Prevention and Control
The Cancer Prevention and Control Program has a funding base of $17,748,186 in annual total costs (current as of July
2011). This sum includes $6,541,103 in NCI funding and $8,113,974 in other NIH funding. Due to space constraints,
only selected new awards since January 1, 2010 of $100,000 or greater in annual total costs are listed here.
133
CLINICAL TRIALS
134
HE UCCCC HAS SUSTAINED A VIGOROUS CLINICAL
research program for many years, and has long been recognized for its strength
in basic and clinical research. Most recently, these activities have been expanded to population
research including epidemiology and prevention trials. The tight and dynamic linkages connecting our basic scientists with our enhanced team of translational and clinical researchers have led
to major contributions in early phase clinical trials and drug development. The integration of
population researchers is taking these trials to the population and community level.
Clinical Trials
T
UCCCC therapeutic clinical trials are conceived and conducted by multidisciplinary teams, which
comprise a group of clinical investigators representing Medical Oncology, Radiation Oncology,
Radiology, Pathology, Biostatistics, and appropriate surgical specialties. All of our research
programs conduct clinical research. These clinical efforts focus on studies of new drugs with
clinical and translational endpoints, sequencing of multidisciplinary treatment, transplantation,
organ preservation, and treatment intensification as strategies to increase cure rates and response.
There is a strong focus on pharmacogenomics and the development of personalized therapeutics.
Within the past few years, there has been a remarkable increase in tangible benchmarks, such as
multi-investigator, multi-disciplinary grants, as well as investigator-initiated clinical trials.
UCCCC SCIENTIFIC REPORT 2010 – 2011
The clinical trials activity of the UCCCC is managed through the Cancer Clinical Trials Office
(CCTO). The CCTO provides oversight and quality control for these studies through the provision of policies and procedures, by centralizing regulatory and reporting functions, supervision of
staff, auditing, and tracking of these activities with a centralized database. The overall objective
of the CCTO is to provide the infrastructure to support successful cancer clinical research across
departments within the University,
as well as through national coop- The tight and dynamic linkages connecting
erative groups. CCTO services and
areas of operation can be divided into our basic scientists with our enhanced team
four distinct but somewhat overlapof translational and clinical researchers have
ping areas: (1) regulatory affairs; (2)
affiliate institution coordination and led to major contributions in early phase
oversight; (3) protocol tracking and
management; and (4) quality control. clinical trials and drug development.
Our drug development program is unique in the Chicago metropolitan area and is among the
largest in the United States. Patients travel from throughout the world to be evaluated for enrollment in phase I and phase II trials of novel anticancer agents. Annually, close to 2000 patients
are enrolled on clinical trials, with 800-1000 entered on therapeutic trials. Clinical trials span
the gamut from preclinical development to investigator-initiated phase I clinical trials to phase
II trials in the regional phase II network to phase III studies within CALGB. Many trials also
incorporate correlative laboratory studies which include genotyping studies, population pharmacology and pharmacogenetics, and measurement of biomarker endpoints. In 2010, clinical trials
enrollment included 900 patients to 179 therapeutic protocols; 485 patients were treated on 94
phase II protocols, and 190 patients were treated on 27 phase I studies.
135
Clinical Trials
In 2010, regulatory managers in the CCTO opened 116 new protocols (95 therapeutic) and
were responsible for ongoing regulatory activities of an additional 325 studies already open to
enrollment, as well as the regulatory activities (e.g., IRB continuing renewals, amendments, safety
reports) for over 350 studies closed to enrollment but not terminated with the IRB. These trials
represent over 50 principal investigators from multiple departments (Medicine, Radiology, Radiation and Cellular Oncology, Surgery, Pediatrics, and Obstetrics and Gynecology).
NUMBER OF THERAPEUTIC PROTOCOLS
(N=315*) and patient accrual (N=900) by sponsor in 2010
TOTAL NO. TRIALS
NO. INVESTIGATOR
INITIATED
NO. OF PTS ENROLLED
(INCLUDING AFFILIATES)
INSTITUTIONAL
44 (14%)
26
216 (24%)
NCI
42 (13%)
9
315 (35%)
COOPERATIVE GROUP
125 (40%)
2
131 (15%)
INDUSTRY
104 (33%)
4
238 (26%)
315
41 (13%)
900
STUDY SPONSOR
UCCCC SCIENTIFIC REPORT 2010 – 2011 TOTAL
136
*Note that of the 315 trials open to accrual in 2010, approximately 13% were investigator-initiated. In addition, close to 60% of our
accrual to therapeutic protocols is to NCI and institutional studies.
The UCCCC and CCTO have been instrumental in the success of several major grants and
contracts including the Phase I Clinical Trials of Anticancer Agents; the Phase II Contract
(N01), Early Therapeutics Development with Phase II Emphasis; the CALGB grant, The Chicago
Prostate Cancer Association (CPCa): A Cooperative Effort for Conducting Prostate Cancer
Focused Clinical Trials; and the SPORE in Prostate Cancer (in collaboration with the Lurie
Comprehensive Cancer Center at Northwestern University). Through association with our Phase
II N01, we were instrumental in receiving an award for a metastatic pancreatic cancer trial funded
under the American Recovery and Reinvestment Act of 2009 (ARRA, Public Law 111-5). The
Phase II program is one of our larger programs and continues to enroll approximately 200 patients
annually. In our N01 Competing Renewal awarded in 2011, we will be further expanding the
network to include the Lurie Comprehensive Cancer Center and Indiana University. The CCTO
supports clinical trials activity associated with all UCCCC research programs.
RESOURCES AND SERVICES
Shared Resources
Shared Resources
The UCCCC supports 13 core facilities, which serve as centralized
centers of expertise and provide researchers access to a comprehensive set of cutting-edge technical resources. These facilities
are funded in large part by the UCCCC and include the Biostatistics Core Facility, Cancer Clinical Trials Office, Epidemiology and
Research Recruitment Core, Frank W. Fitch Monoclonal Antibody
Facility, Flow Cytometry Facility, Genomics Core Facility, Human
Integrated Microscopy Facility, Magnetic Resonance Imaging and
Spectroscopy Facility, Pharmacology Core Facility, Scientific Image
Reconstruction and Analysis Facility, and Transgenic Mouse and
Embryonic Stem Cell Facility.
Biostatistics Core Facility
The Biostatistics Core Facility provides collaborative statistical support to investigators for the
design, conduct, and analysis of clinical trials, observational, and population-based studies,
and basic science research projects. The Facility assists in experimental design, analyses of data,
manuscript and grant preparation, review of clinical protocols, and training investigators in fundamental statistical concepts, study design, and clinical trials methodology. Director: Ronald
Thisted, PhD. Website: http://health.bsd.uchicago.edu/Biostatistics-Laboratory.
UCCCC SCIENTIFIC REPORT 2010 – 2011
Immunologic Monitoring Core, Human Tissue Resource Center,
Cancer Clinical Trials Office (CCTO)
The CCTO provides oversight and quality control for clinical trials activity at the UCCCC by
centralizing regulatory and reporting functions. The overall objective of the CCTO is to provide
the infrastructure to support successful clinical research across departments. The CCTO facilitates
regulatory management, coordination and oversight of affiliate institutions enrolling patients on
trials at the UCCCC, protocol tracking and management, and quality control. Director: Marcy
List, PhD. Website: http://cancer.uchicago.edu.
Frank W. Fitch Monoclonal Antibody Facility
The Frank W. Fitch Monoclonal Antibody Facility provides standard and custom services for
comprehensive hybridoma and protein production. Services include novel monoclonal antibody
production, protein purification and conjugation, subcloning of hybridoma cell lines, cell
storage, and an extensive antibody/hybridoma bank. Director: Anne Sperling, PhD. Website:
http://fitchantibodies.bsd.uchicago.edu.
137
Shared Resources
Flow Cytometry Facility
The Flow Cytometry Facility provides access to state-of-the-art technology and quantitative analytical approaches to measure molecular and cellular function. The Facility is designed to meet the
wide-spread needs for specialized cytologic analysis by providing instrumentation for cell sorting
and bench-top analysis of subcellular components using multiparametric fluorescence detection
technology. Director: Anne Sperling, PhD. Website: http://ucflow.uchicago.edu.
Genomics Core Facility
UCCCC SCIENTIFIC REPORT 2010 – 2011 The Genomics Core Facility provides state-of-the-art microarray, DNA sequencing, and genotyping platforms with specialized databases for storing, managing, and manipulating both clinical
information and diverse types of genetic and genomic data. The Facility offers sophisticated
hardware, bioinformatic software applications, and database solutions. Services include next-generation sequencing, high-throughput gene expression and genotyping arrays, DNA preparation
and sequencing, protein array profiling, customized RNA/DNA extraction and quantification,
and genomic and bioinformatic analyses. Director: Pieter Faber, PhD. Websites: http://fgf.bsd.
uchicago.edu, http://cancer-seqbase.uchicago.edu, https://ibi.uchicago.edu.
Human Immunologic Monitoring (HIM) Facility
The HIM Facility is a specialized laboratory that performs analyses of immunologic endpoints and
other pharmacodynamic parameters for cancer-based clinical trials. The Facility assists with project
development, evaluates immune response parameters in response to immunotherapeutic interventions, monitors biologic effects of pharmacologic agents using lymphocytes or other hematopoietic
cell subsets as a surrogate tissue, and interfaces with the current Good Manufacturing Practice
(cGMP) Facility to prepare clinical-grade products, such as cancer vaccines, for administration to
patients. Director: Thomas Gajewski, MD, PhD. Website: http://him.bsd.uchicago.edu.
Human Tissue Resource Center (HTRC)
The HTRC provides investigators with a centralized infrastructure to optimize the efficiency and
costs related to research involving human biospecimens. The HTRC comprises three integrated
components including the Biospecimen Bank (BSB), Laser Capture Microdissection (LCM),
Pathology Image Analysis (PIA), and Immunohistochemistry (IHC). HTRC staff assists with the
procurement, processing, distribution, and analysis of human biospecimens. Services include centralized tissue banking, pathological verification of tissue samples, tissue microarray fabrication,
laser capture microdissection, histological services, and quantitative image analyses. Director:
Mark Lingen, DDS, PhD. Website: http://pathcore.bsd.uchicago.edu.
Integrated Microscopy Facility
The Integrated Microscopy Facility is a supervised, user-based core that provides imaging capabilities to investigators through microscopy instrumentation, data analysis and storage, and expert
training and assistance. The Facility provides high-quality optics and equipment that most labs
do not possess, including confocal and state-of-the-art two-photon spectral and STED superresolution spectral microscopes. Available techniques provided by the Facility include classic color
histological stain imaging, contrast generation in unstained cells, and fluorescence technologies
that allow for applications ranging from localization of multiple targets to readouts of biochemical
or physiologic parameters in either fixed or living preparations. Director: Benjamin Glick, PhD.
Website: http://digital.uchicago.edu.
138
The MRIS Facility provides magnetic resonance imaging for studies of both animal models of
cancer and clinical research involving human subjects. The Facility delivers very high-resolution
anatomic images, images of hemodynamic parameters such as perfusion rate and capillary permeability, and images of tumor oxygenation. The scanners can also provide metabolic measurements
with MR spectroscopy and MR spectroscopic imaging. Additional services include molecular
imaging, functional MR imaging of the brain, multimodality imaging with microPET/SPECT/
CT and EPR, development and testing of new contrast agents and imaging methods, and veterinary services. Directors: Gregory Karczmar, PhD, and Brian Roman, PhD. Website: http://mris.
bsd.uchicago.edu.
Shared Resources
Magnetic Resonance Imaging and Spectroscopy (MRIS) Facility
Pharmacology Core Facility
The Pharmacology Core Facility evaluates pharmacokinetic, pharmacodynamic, and pharmacogenetic parameters in support of investigators conducting clinical and preclinical drug
development studies. The Facility analyzes drug and metabolite concentrations in biological fluids
and develops pharmacological assays of anticancer agents. Director: Mark Ratain, MD. Website:
http://pharmacology.bsd.uchicago.edu.
The SIRAF provides services for medical imaging, including a high performance computer cluster
and direct archival capabilities, in collaboration with the Magnetic Resonance Imaging and
Spectroscopy (MRIS) Facility and the University of Chicago’s Optical Imaging Core Facility.
SIRAF offers investigators free access to all computers, centralized archiving, and specialized
software packages that support image acquisition, construction of databases, reconstruction
techniques, image analysis (including computer-aided diagnosis), and technology assessment. The
Facility supports basic research involving modeling and simulations, applied research involving
the development of new image analysis methods, and the development of grid-based technologies.
Director: Robert Nishikawa, PhD. Website: http://siraf-login.bsd.uchicago.edu:8010/siraf-wiki.
Transgenic Mouse and Embryonic Stem Cell Facility
UCCCC SCIENTIFIC REPORT 2010 – 2011
Scientific Image Reconstruction and Analysis Facility (SIRAF)
The Transgenic Mouse and Embryonic Stem Cell Facility produces genetically manipulated mice
through transgenic technology or embryonic stem (ES) cell manipulation for investigators. The
Facility provides a comprehensive set of technical services, offers gene construction and targeting services, develops and maintains ES cell lines, provides various breeding services, and offers
training in Mouse Handling and Breeding. Director: Eric Svensson, MD, PhD. Website: http://
transgenic.bsd.uchicago.edu.
Epidemiology and Research Recruitment Core (ERRC)
The ERRC assists investigators with study design, surveillance development, recruitment of
study participants, and collaborations with the UCCCC’s community outreach program. The
ERRC also works with the Human Tissue Resource Center to assist investigators with biological specimen collection for a wide range of hospital- and community-based cancer population
studies. Director: Brian Chiu, PhD. Website: http://cancer.uchicago.edu/research/core-facilities/
epidemiology.shtml.
139
Education and Training
Education and Training
UCCCC members participate in a variety of training and educational opportunities, including graduate and post-graduate training
programs offered by departmental committees. These committees span a range of disciplines, including Cancer Biology; Clinical
Pharmacology
and
Pharmacogenomics;
Genetics,
Genomics
& Systems Biology; Immunology; Molecular Biology; Medical
Physics; and Molecular Metabolism and Nutrition. Many UCCCC
members participate in one or more of these training programs,
the majority of which are supported by NIH training grants. Fellowship training programs in surgical oncology, medical oncology,
radiation oncology, and pediatric oncology are also offered by the
UCCCC SCIENTIFIC REPORT 2010 – 2011 UCCCC. In addition, members participate in a variety of seminar
series, joint programmatic meetings, and departmental retreats,
which are instrumental in fostering inter- and intraprogrammatic
research collaborations.
Committee on Cancer Biology
The Committee on Cancer Biology offers a multidisciplinary and integrated graduate training
program of study leading to a PhD in cancer biology. Directed by Geoffrey Greene, PhD, the Committee is supported by an NCI training grant and has a broad curriculum focusing on several areas
of cancer biology, including apoptosis, cancer genetics, cell cycle, chromosome damage/repair, drug
resistance, hormone action, metastatic progression, cell signaling, and tumor biology/immunology.
The Committee fosters interactions between basic, translational, and clinical researchers.
Committee on Clinical Pharmacology and Pharmacogenomics
The Committee on Clinical Pharmacology and Pharmacogenomics administers a 2-year postgraduate training program, accredited by the American Board of Clinical Pharmacology and
supported by an NIH training grant, for MDs, PhDs and PharmDs. The Committee is led by M.
Eileen Dolan, PhD, and consists of diverse faculty from departments across the University. The
goal of the interdisciplinary program is to train individuals in various subspecialties of clinical
pharmacology, including principles of therapeutics, molecular pharmacology, and pharmacogenomics. The program offers training through various didactic exercises, seminars, and research
projects.
Committee on Genetics, Genomics & Systems Biology
The Committee on Genetics, Genomics & Systems Biology, offers a PhD program in genetics
that combines training in sophisticated modern genetic analysis with genetic-based strategies for
investigating clinical and basic science questions in the context of physiological, developmental,
and evolutionary systems. The program is supported by an NIH training grant and consists
of faculty from 16 different departments and represents a broad interdisciplinary approach to
140
Committee on Immunology
Committee on Medical Physics
The Committee on Medical Physics offers research training leading to a MS or PhD degree. The
program, led by Maryellen Giger, PhD, and supported by an interdisciplinary NIH training grant,
applies the principles of the physical sciences to biomedicine. The Committee includes members
of the UCCCC Advanced Imaging Program and faculty from the Departments of Radiology,
and Radiation and Cellular Oncology. Specific areas of focus include diagnostic radiography,
magnetic resonance imaging and spectroscopy, computer-aided diagnosis and quantitative image
analysis, electron paramagnetic resonance imaging, nuclear medicine imaging, and computer
applications in radiation therapy.
UCCCC SCIENTIFIC REPORT 2010 – 2011
The Committee on Immunology provides multidisciplinary training toward a PhD degree in fundamental
immunology and approaches to understanding immunological diseases. The program has been continuously
funded by NIH training grants for over 30 years
and represents one of the oldest and most prestigious
immunology programs in the country. The Committee
integrates the basic biological sciences with the clinical
sciences to develop new approaches for the diagnosis and
treatment of various immune diseases and cancer. Areas
of basic and applied immunology research include autoimmunity; hematopoiesis, lymphoid and
myeloid development; T-cell differentiation; signal transduction in lymphoid development and
activation; and tumor immunity.
Education and Training
teaching and research. Strengths of the program include
gene expression and developmental genetics, chromosome
organization and behavior, population and evolutionary
genetics, and genetics of human disease with an emphasis
on genetic alterations in cancer.
Committee on Molecular Metabolism and Nutrition
The Committee on Molecular Metabolism and Nutrition is an interactive research program supported by an NIH training grant that offers interdisciplinary doctoral training in the molecular
basis of biological processes related to nutritional status, metabolic homeostasis, and human
disease. The program focuses on metabolism and metabolic diseases including, for example,
diabetes and obesity, using biochemical, clinical, physiological, cell, and molecular biological
approaches. The Committee works closely with the Digestive Disease Research Core Center and
Kovler Diabetes Center at The University of Chicago.
Department of Health Studies
The Department of Health Studies, chaired by Ronald Thisted, PhD, is a cross-disciplinary program
focused on biostatistics, epidemiology, and health services research that studies the environmental
and organizational factors influencing the health of human populations. The Department offers
an MS degree in Health Studies for Clinical Professionals (MSCP), and a certificate program,
the Clinical Research Training Program (CRTP). The MSCP program is designed to educate
doctoral-level individuals in the theory, methods, and concepts of biostatistics, epidemiology, and
141
Education and Training
health services research required to develop clinical and epidemiologic research studies. The CRTP,
an NIH-supported program designed for clinicians or clinical researchers, offers formal training
opportunities in areas relevant to the design, implementation, and analysis of clinical research. In
addition, the Department offers a PhD program in biostatistics, epidemiology, and health services
research based on a core curriculum in population-based health research.
UCCCC SCIENTIFIC REPORT 2010 – 2011 Graham School of General Studies
142
MacLean Center for Clinical Medical Ethics
The MacLean Center for Clinical Medical Ethics is internationally recognized as a leading
program for research and training in medical ethics. The Center is directed by Mark Siegler, MD,
and consists of several UCCCC members and faculty in medicine, law, business, public policy,
and social sciences. Established in 1984 with support from the family of Dorothy J. MacLean,
the Center offers both a 2-year master’s degree and a 1-year part-time fellowship program. The
master’s degree program provides a health services research curriculum and is intended for physicians interested in pursuing an academic career with a focus on health policy and clinical medical
ethics. The 1-year, part-time fellowship program offers clinicians, not necessarily pursuing
academic medicine, training in medical ethics.
The University of Chicago Graham School of General Studies offers a Clinical Trials Management Certificate Program. This post-baccalaureate program provides comprehensive training in
clinical practices, drug development, statistical concepts for clinical research, and clinical site
management and monitoring. The program enables graduates to initiate clinical research, apply
effective monitoring methods, and understand regulations and good clinical practices. All staff in
the Cancer Clinical Trials Office have completed this training program.
UCCCC members serve as principal investigators for 13 cancer-related NIH T32 and T35 training
grants. These grants support training programs in diverse areas of basic, behavioral, and clinical
research related to addictions research, cancer biology, clinical therapeutics, genetics, immunology,
medical oncology, medical physics, molecular biology, and nutrition.
TITLE
PRINCIPAL
INVESTIGATOR
TOTAL
ANNUAL
COST
CLASS
FUNDING AGENCY
$476,312
T32
Eugene Chang
$388,918
T32
National Institute
of Diabetes and
Digestive and Kidney
Diseases
Marcus Clark
$1,082,136
T32
National Institute
of General Medical
Sciences
RESEARCH TRAINING IN
MEDICAL PHYSICS
Maryellen Giger
$264,696
T32
National Institute of
Biomedical Imaging
and Bioengineering
MOLECULAR AND CELLULAR
BIOLOGY TRAINING PROGRAM
Benjamin Glick
$1,229,690
T32
National Institute
of General Medical
Sciences
INTERDISCIPLINARY PROGRAM
IN IMMUNOLOGY
RESEARCH TRAINING IN DIGESTIVE
DISEASES AND NUTRITION
MEDICAL SCIENTIST NATIONAL
RESEARCH SERVICE AWARD
GRADUATE TRAINING PROGRAM IN
CANCER BIOLOGY
Geoffrey Greene
$520,558
T32
National Cancer
Institute
CARDIOVASCULAR SCIENCES
TRAINING GRANT
Elizabeth McNally
$385,910
T32
National Heart, Lung
and Blood Institute
SHORT-TERM AGING-RELATED
RESEARCH PROGRAM
David Meltzer
$62,694
T35
National Institute
on Aging
BASIC MEDICAL ONCOLOGY
RESEARCH TRAINING IN MEDICAL
ONCOLOGY
Olufunmilayo
Olopade
$369,817
T32
National Cancer
Institute
CLINICAL THERAPEUTICS
Mark Ratain
$185,567
T32
National Institute
of General Medical
Sciences
Nancy Schwartz
$433,317
T32
National Institute of
Child Health & Human
Development
Julian Solway
$643,401
T32
National Heart, Lung
and Blood Institute
Paul Vezina
$489,041
T32
National Institute on
Drug Abuse
GRADUATE TRAINING IN GROWTH
AND DEVELOPMENT
RESEARCH TRAINING IN
RESPIRATORY BIOLOGY
NEUROPSYCHOPHARMACOLOGY
TRAINING FOR DRUG ABUSE
RESEARCH
UCCCC SCIENTIFIC REPORT 2010 – 2011
Albert Bendelac
National Institute of
Allergy and Infectious
Diseases
Education and Training
Training Grants
In addition, the NCI-funded Paul Calbresi K12 Scholars Program supports the training of
junior investigators pursuing careers in clinical and translational research. Led by Olufunmilayo
Olopade, MBBS, the mentored training program provides “hands-on” clinical research training
that results in a master’s degree in health studies.
143
Patient and Community Services
Patient and Community Services
The UCCCC is committed to translating breakthroughs in interdisciplinary basic and clinical cancer research into state-of-the-art
patient care. UCCCC clinicians and researchers strive to improve
the quality-of-life for patients by also providing access to numerous
resources aimed at supporting the physical, social, and emotional
needs of cancer patients and survivors. Vital to these efforts is
sustained engagement with the community to enhance public
awareness of these resources and advances in cancer research.
UCCCC SCIENTIFIC REPORT 2010 – 2011 Breast Cancer Survivorship Program
The Breast Cancer Survivorship Program, led by Susan Hong, MD, MPH, offers a personalized
approach to breast cancer survivorship from the time of diagnosis through treatment. A multidisciplinary team of specialists, including medical and radiation oncologists, radiologists, surgeons, and
psycho-oncologists, educates patients on topics related to long-term side effects of treatment, family
history of disease, fertility issues, nutrition and healthy lifestyles, and disease recurrence. Services
are focused on individualized treatment and wellness.
Cancer Resource Center
The UCCCC, in partnership with the American Cancer
Society, offers a comprehensive resource center to provide
patients and their families access to cancer-related
information and social services. The Center is staffed
by a certified health education specialist and a licensed
clinical social worker who are dedicated to helping
patients obtain individualized cancer information,
including facts about specific types of cancer, education
on treatment and pain management, information about
innovative clinical trials, and community resources. The
Center facilitates access to support groups for caregivers
and patients, and offers onsite access to a wide variety
of activities through a partnership with Gilda’s Club
Chicago, including additional support/networking
groups, healing arts workshops, and various educational
programs. The Center also provides one-on-one counseling, patient navigation services, assistance with medical insurance, referrals for social and support
services, and various outreach activities.
Cancer Risk Clinic
The Cancer Risk Clinic is a comprehensive cancer risk assessment and prevention program
designed for individuals who may be at an increased risk for cancer. The Clinic is directed by Dr.
Olufunmilayo Olopade and staffed by a team of specialists who assess cancer risk, provide genetic
counseling, educate patients about cancer risk and prevention, and develop personalized riskreduction strategies. Strategies may include systematic monitoring or screening for early detection,
lifestyle changes, and the use of cancer preventive procedures or drugs. The Clinic also has an
active community outreach program, which has increased patient enrollment in clinical studies
for evaluating new therapies, prevention methods, and risk-reduction strategies.
144
The Childhood Cancer Survivors Center, led by Tara Henderson, MD, MPH, is an integrated program for pediatric
and adult survivors of childhood cancer. The program is
aimed at the prevention and treatment of long-term issues
associated with cancer therapy, including heart and renal
problems, secondary cancers, endocrine disorders, fertility
issues, and social or psychological concerns. Specialists
focus on educating survivors and their families about these
health issues and developing individualized recommendations for health maintenance and screening.
Patient and Community Services
Childhood Cancer Survivors Center
Office of Community Engagement
and Cancer Disparities
UCCCC SCIENTIFIC REPORT 2010 – 2011
The UCCCC established the Office of Community Engagement and Cancer Disparities (OCECD)
in 2010 as a renewed effort to serve local communities through research, education, advocacy, and
outreach. Directed by Karen E. Kim, MD, MS, the program represents the UCCCC’s expanded
commitment to understand and serve the unique needs of its surrounding neighborhoods. The
OCECD has formed strategic partnerships with various organizations within The University of
Chicago and with community- and faith-based organizations to develop innovative programs to
increase access to healthcare, reduce cancer risk, increase participation in cancer clinical trials,
and improve the quality of life of cancer patients and survivors. For example, the OCECD successfully launched the Empowering Neighborhood Resources in Combating Health Disparities
(ENRICH’D™) program to increase breast cancer awareness and improve mammography utilization rates among various racial and ethnic groups in the Chicago area. Chicago-area organizations
also participate in the OCECD’s wellness program, Everyone Developing an Understanding of
Cancer Awareness Treatment and Education (ED-U-CATE), which educates employees about
cancer risks, screening, and treatment. Various workshops and conferences within surrounding
communities are also organized to disseminate information on cancer advances, clinical trials,
and research trends. These activities maintain a bidirectional exchange of ideas and perspectives
and help the UCCCC better understand and meet the needs of its patients.
Program in Integrative Sexual Medicine
The University of Chicago Medical Center’s Program in Integrative Sexual Medicine (PRISM) for
Women and Girls with Cancer is the first multidisciplinary clinical and research program in Illinois
dedicated to the comprehensive assessment, prevention, and treatment of sexual health concerns in
female cancer patients and survivors. Under the direction of Stacy Tessler Lindau, MD, MAPP, specialists provide education on the potential impact of cancer therapies on sexuality, treatment for sexual
problems, and counseling on common sexual concerns of girls and women who have had cancer. Physician researchers apply newly identified strategies from clinical studies to treat sexual dysfunction related
to cancer symptoms and therapy. These strategies may be offered in collaboration with specialists in
physical therapy, psychiatry, and urogynecology as part of a multidisciplinary treatment approach.
Specialized Oncology Care & Research in the Elderly
Directed by William Dale, MD, PhD, the Specialized Oncology Care & Research in the Elderly (SOCARE)
clinic addresses the specific needs of elderly cancer patients and survivors. The Clinic is staffed by physicians with expertise in geriatric medicine, geriatric oncology, and palliative care who help patients and their
families understand the risks and limitations of cancer therapy in older adults. Comprehensive, individualized
treatment plans are developed for patients that take into account co-existing disease, cognitive deficits, and
functional limitations.
145
Dedicated Research Facilities
The University of Chicago Medical Center and
Dedicated Research Facilities
The University of Chicago Medical Center occupies over 30 buildings,
which house all hospital and clinical areas of the campus as well as
teaching and research space. The UCCCC’s primary clinical facilities
within the Center include the Bernard A. Mitchell Hospital, Comer
Children’s Hospital, and the outpatient clinics in the Duchossois
Center for Advanced Medicine (DCAM). Dedicated UCCCC research
space spans two state-of-the-art facilities, including the Ellen and
Melvin Gordon Center for Integrative Science (GCIS) and the Gwen
and Jules Knapp Center for Biomedical Discovery (KCBD).
UCCCC SCIENTIFIC REPORT 2010 – 2011 Bernard A. Mitchell Hospital
The Bernard A. Mitchell Hospital, the primary adult inpatient facility which includes an emergency department and intensive care unit, provides more than 60 beds dedicated to adult medical
oncology. Patients participating in clinical pharmacology
studies are hospitalized in the General Clinical Research
Center (GCRC), an NIH-funded facility with dedicated
nursing and research staff for clinical research. The
facility provides more than 4,000 square feet of space for
specialized research and patient care, and operates a core
laboratory for rapid routine assays and sample processing.
Comer Children’s Hospital
Comer Children’s Hospital is a tertiary care teaching
facility specializing in the treatment of childhood diseases
through patient education, care, and research. The stateof-the-art facility provides 242,000 square feet of space
that accommodates more than 150 beds, 25% of which
are dedicated to the treatment of children and adolescents
with cancer. The facility houses one of the country’s
largest and most advanced pediatric intensive care units equipped to treat complex medical cases
and children with multiple traumas.
Duchossois Center for Advanced Medicine (DCAM)
DCAM is a state-of-the-art facility that integrates the majority of the Medical Center’s diagnostic
and outpatient treatment services. The 550,000-square-foot facility houses outpatient clinics for
gynecologic, medical, and radiation oncology. Facilities include an apheresis unit, modern radiation therapy units, and contemporary chemotherapy infusion suites. The multidisciplinary Breast
Center is also located in DCAM and provides examination and consulting rooms, mammography
services, patient information, and cancer risk assessment conveniently in one location to serve
patients with breast cancer.
146
Currently under construction is
the New Hospital Pavilion, a $700
million,
1.2-million-square-foot
facility that will provide an optimal
setting for collaborative clinical
research and patient care. The
high-technology facility will house
many of The University of Chicago
Medical Center’s most distinguished
clinical programs, including those
that provide complex specialty care
with a focus on cancer, gastrointestinal disease, medical imaging,
neuroscience, and advanced surgery.
Completion of the facility is planned
for early 2013.
The GCIS was completed in 2005
and represents one of the few research
facilities in the country that bridges
physical and biological sciences
under one roof. The seven-story,
430,000-square-foot building houses 20 UCCCC members in state-of-the-art modular laboratories as well as the Ben May Department for Cancer Research, Department of Biochemistry and
Molecular Biology, Howard Hughes Medical Institute, Institute for Biophysical Dynamics, and
select laboratories of the Physical Sciences Division.
UCCCC SCIENTIFIC REPORT 2010 – 2011
Ellen and Melvin Gordon
Center for Integrative
Science (GCIS)
Dedicated Research Facilities
New Hospital Pavilion
Gwen and Jules Knapp Center for Biomedical Discovery (KCBD)
Opened in 2009, the $244 million KCBD is a 12-story facility that fosters groundbreaking
initiatives in the Division of Biological Sciences. The 330,000-square-foot facility includes a stateof-the-art vivarium and dedicated core facility space for the Genomics, Transgenic Mouse/ES
Cell, and Integrated Microscopy Facilities. Research programs from the Departments of Medicine
(Section of Hematology/Oncology) and Pediatrics (Section of Pediatric Hematology/Oncology),
UCCCC, Ludwig Center for Metastasis Research, and Institute for Genomics and Systems
Biology are located in the KCBD. The UCCCC has 22,000 square feet of dedicated space. Collectively, the KCBD houses dozens of UCCCC researchers. The KCBD, GCIS, and Knapp Center
for Molecular Medicine are connected by pedestrian bridges that facilitate collaboration among
80% of the UCCCC’s laboratory researchers who are located in these state-of-the-art facilities.
147
HIGHLIGHTS
148
New Faculty Recruitments and UCCCC
Members in 2010-2011
nDaniel Catenacci, MD, is an instructor of medicine and member of the UCCCC
Pharmacogenomics and Experimental Therapeutics Program. His research focuses on receptor
tyrosine kinases, including RON and MET, and the development of novel therapeutic agents for
the treatment of gastroesophageal malignancies.
nJill de Jong, MD, PhD, focuses her research on the genes that regulate normal hematopoietic
stem cell (HSC) function in the bone marrow and whether those genes may contribute to the
development of leukemia under aberrant expression. Dr. de Jong is an assistant professor of
medicine and a member of the UCCCC Hematopoiesis and Hematological Malignancies
Program. She utilizes the zebrafish model as a unique discovery mechanism to uncover new
genetic regulators of HSCs.
nJoshua Hemmerich, PhD, was recruited as an assistant professor of medicine. Dr.
Hemmerich is a cognitive psychologist and member of the UCCCC Cancer Prevention and
Control Program with research interests centered on treatment decisions in older patients,
specifically with non-small cell lung cancers and their clinical outcomes.
nPeter O’Donnell, MD, joins the UCCCC Pharmacogenomics and Experimental
Therapeutics Program as an instructor of medicine. Dr. O’Donnell’s research interests are in
pharmacogenomics, specifically the incorporation of host genetic factors and use of other novel
biomarkers to identify appropriate individualized therapies. Dr. O’Donnell is working closely
with Dr. Mark Ratain on clinical implementation of pharmacogenomic markers.
nBrandon Pierce, PhD, an assistant professor of health studies and member of the UCCCC
Cancer Prevention and Control Program, is a genetic epidemiologist focused on identifying and
characterizing the genetic and molecular factors that play a role in the risk and prognosis for breast
and prostate cancer. His research interests include the role of DNA copy number and telomere
length in cancer causation and novel methods for causal inference in genetic epidemiology.
UCCCC SCIENTIFIC REPORT 2010 – 2011
nJennifer McNeer, MD, is a clinical researcher focused on improving treatment strategies
for high-risk leukemia patients. Dr. McNeer, an assistant professor of pediatrics, is a member
of the UCCCC Hematopoiesis and Hematological Malignancies Program and specializes in
the development of new, experimental therapeutics for the treatment of pediatric leukemia and
lymphoma.
New Faculty Recruitments and UCCCC Members
nIssam Awad, MD, is a professor of surgery and member of the UCCCC Advanced Imaging
Program. Dr. Awad, an expert in neurovascular disease, combines molecular biology methods
with state-of-the-art imaging techniques to study angiomatous tumors.
nIris Romero, MD, is an assistant professor of obstetrics and gynecology. As a physician
scientist and member of the UCCCC Cancer Prevention and Control Program, Dr. Romero is
identifying novel approaches to prevent ovarian cancer with an emphasis on molecularly targeted
interventions.
nMichael Spiotto, MD, PhD, an instructor of radiation and cellular oncology, investigates
novel methods to treat head and neck cancer. His research focuses on developing in vivo screens
to identify genes involved in the metastasis of primary tumors. Dr. Spiotto, as a member of
the UCCCC Molecular Mechanisms of Cancer Program, is also developing targeted inhibitors
against the human papilloma virus (HPV) oncogenic proteins E6 and E7.
nRussell Szmulewitz, MD, is an instructor medicine and member of the UCCCC
Pharmacogenomics and Experimental Therapeutics Program. He is a translational scientist
with research interests in prostate cancer biomarker development and prostate cancer metastatic
latency and progression. Dr. Szmulewitz is currently investigating the molecular mechanisms of
how stress-activated protein kinase members inhibit prostate cancer metastatic colonization.
149
Selected Awards and Honors
UCCCC SCIENTIFIC REPORT 2010 – 2011 nVictoria Villaflor, MD, joins the UCCCC Pharmacogenomics and Experimental Therapeutics
Program as an assistant professor of medicine. Her research focuses on the evaluation of targeted
agents for the treatment of lung and head and neck cancers.
nSamuel Volchenboum, MD, PhD, MS, an assistant professor of pediatrics, uses a systems
biology approach to study pediatric cancer in the UCCCC Molecular Mechanisms of Cancer
Program. Using neuroblastoma as a paradigm system, he is developing novel techniques for the
integration of orthogonal datasets as well as novel algorithms to facilitate high-throughput mass
spectrometry analysis for improving patient diagnostics and assessing response to therapy.
nPatrick Wilson, PhD, an assistant professor of medicine and member of the UCCCC
Immunology and Cancer Program, has developed technologies that allow rapid cloning and
sequencing of antibody molecules from plasmablasts in patients. He aims to use this strategy to
identify B cell antibody specificities in cancer patients, which will facilitate the development of
new therapeutic monoclonal antibodies.
  Selected Awards and Honors
Molecular Mechanisms of Cancer Program
Kay Macleod, PhD, associate professor of the Ben May Department for Cancer Research,
was named to a 4-year term on the National Institutes of Health Cancer Molecular Pathobiology
(CAMP) Study Section 2011.
Carrie Rinker-Schaeffer, PhD, associate professor of surgery and director of urologic
research, was elected the 2011 president of The Metastasis Research Society (MRS), which is dedicated to understanding tumor metastasis and bringing new potential therapeutics into clinical
trials.
Hematopoiesis and Hematological Malignancies Program
Jianjun Chen, PhD, assistant professor of medicine, was awarded a 2011 Research Scholar
Award from the American Cancer Society (ACS) to support his research in determining the role
of miR-126 in the development of core-binding factor (CBF) leukemias.
Richard Larson, MD, professor of medicine and director of The University of Chicago Hematologic Malignancies Clinical Research Program, was elected treasurer of the American Society of
Hematology in 2010 to serve a 4-year term.
Michelle Le Beau, PhD, professor of medicine, director of the Cancer Cytogenetics Laboratory, and director of the UCCCC, was named the inaugural Arthur and Marian Edelstein
Professor for her contributions as a scientist and leader and elected as vice president/president-elect
150
Janet Rowley, MD, DSc, the Blum-Riese Distinguished Service Professor of Medicine,
Molecular Genetics & Cell Biology, and Human Genetics, received the Jessie Stevenson Kovalenko Medal from the National Academy of Sciences in 2010 for her contributions in identifying
chromosomal abnormalities in leukemias and lymphomas. Dr. Rowley also received the 7th
annual American Association of Cancer Research (AACR) Lifetime Achievement in Cancer
Research Award, Margaret Kripke Legend Award from The University of Texas MD Anderson
Cancer Center, and Enrico Fermi History Maker Award for Distinction in Science, Medicine,
and Technology from the Chicago Historical Society in 2010. In addition, Dr. Rowley was one
of two cancer geneticists to receive the 2010 Pearl Meister Greengard Prize from The Rockefeller
University in recognition of outstanding female scientists. In 2011, Dr. Rowley was awarded
the Alumni Medal by The University of Chicago Alumni Association and received an honorary
doctoral degree in medical sciences from Yale University for her revolutionary work in human
genetics and cancer research. Dr. Rowley was also selected for the Ernest Beutler Lecture and
Prize by the American Society of Hematology for her pivotal work in the diagnosis and treatment
of chronic myeloid leukemia.
Immunology and Cancer Program
Thomas Gajewski, MD, PhD, professor of pathology, was elected in 2010 as president of the
International Society for Biological Therapy of Cancer (iSBTc), an international non-profit dedicated to improving cancer patient outcomes by advancing the application of biological therapy/
immunotherapy. Dr. Gajewski was also selected as The University of Chicago principal investigator in 2011 for the Cancer Immunotherapy Trials Network (CITN), a new initiative funded by
the National Cancer Institute (NCI).
UCCCC SCIENTIFIC REPORT 2010 – 2011
Sonali Smith, MD, associate professor of medicine, was appointed director of The University of
Chicago Lymphoma Program in the Section of Hematology/Oncology. Dr. Smith was also elected
to the Lymphoma Research Foundation Scientific Advisory Board in 2011 for a 5-year term.
Selected Awards and Honors
of the Association of American Cancer Institutes (AACI) in 2011. Dr. Le Beau will be the association’s first female president and will serve 2 years each as AACI vice president/president-elect,
president, and immediate past-president.
Bana Jabri, MD, PhD, professor of medicine, was elected in 2011 to the Association of
American Physicians in recognition of her contributions as an international leader in the study of
celiac disease and mucosal immunology.
Vinay Kumar, MD, PhD, professor and chair of pathology, was named the Donald N. Pritzker
Professor in 2011 for his contributions to scholarship and leadership of the Department of Pathology.
Pharmacogenomics and Experimental Therapeutics Program
Ezra Cohen, MD, associate professor of medicine, was appointed co-director of The University of Chicago Head and Neck Cancer Program in 2010, which specializes in the treatment of
head and neck, lung, and esophageal cancers. Dr. Cohen was also elected editor-in-chief of Oral
Oncology in 2010, the official journal of the European Association of Oral Medicine, International Association of Oral Pathologists, and the International Academy of Oral Oncology.
M. Eileen Dolan, PhD, professor of medicine, was appointed chair of The University of
Chicago Committee on Clinical Pharmacology and Pharmacogenomics in 2010 to oversee the
training of graduate students and clinical and post-doctoral fellows. Dr. Dolan also received the
151
Selected Awards and Honors
2010 Distinguished Alumni Award from the Purdue University School of Pharmacy and the
2011 Purdue University Distinguished Women Scholars Award in recognition of her outstanding
professional and scientific achievements.
Alessandro Fichera, MD, associate professor of surgery, won the Best Video Award at the
2011 American Society of Colon & Rectal Surgeons for his video on “Single Incision Laparoscopic
Total Proctocolectomy for Refractory Crohn’s colitis.”
Chuan He, PhD, professor of chemistry, received the Early Career Award from the Society of
Biological Inorganic Chemistry (SBIC) in 2010 for his distinguished research and impact. Dr. He
was also the recipient of the American Chemical Society’s (ACS) Akron Section Award in 2010
for young scientists.
UCCCC SCIENTIFIC REPORT 2010 – 2011 Bruce Minsky, MD, professor of radiation and cellular oncology, was named by the Association of Residents in Radiation Oncology (ARRO), in partnership with the American Society for
Radiation Oncology (ASTRO), as one of 40 Educators of the Year.
Mitchell Posner, MD, the Thomas D. Jones Professor and vice chairman of surgery, and
section chief of general and oncologic surgery, was elected president of the Society of Surgical
Oncology in 2010.
Mark Ratain, MD, the Leon O. Jacobson Professor of Medicine, was named director of The
University of Chicago’s Center for Personalized Therapeutics in 2010. Dr. Ratain was also selected
as the 2011 recipient of an Honorary Fellow Award from the American College of Clinical Pharmacology in recognition of his contributions to the field of clinical pharmacology. In addition, Dr.
Ratain was selected as the 2011 recipient of the American Society of Clinical Oncology (ASCO)
Translational Research Professorship (TRP), which provides flexible funding to outstanding
translational researchers.
Advanced Imaging Program
Stephen Archer, MD, the Harold Hines Jr. Professor of Medicine and chief of cardiology, was
elected president of the American Heart Association’s (AHA) Metro Chicago board of directors
in 2010. Dr. Archer was also selected by the American College of Cardiology as the recipient of its
2011 Distinguished Scientist Award in recognition of his major contributions to the advancement
of scientific knowledge.
Richard Baron, MD, professor of radiology, was appointed as The University of Chicago’s
dean for clinical practice in 2010.
Maryellen Giger, PhD, professor of radiology, chair of the Committee on Medical Phyics,
and vice chair for basic science research of radiology, was elected to the National Academy of
Engineering in 2010, one of the highest professional distinctions accorded to an engineer.
Patrick La Riviere, PhD, associate professor of radiology, was elected in 2011 to The University of Chicago College Council for a 3-year term to set policies on admissions, curricula, and
degree requirements.
Xiaochun Pan, PhD, professor of radiology, was the 2010 recipient of a technical award from
the IEEE Engineering in Medicine and Biology Society (EMBS) for significant contributions to
medical imaging. Dr. Pan was also elected chair of the National Institutes of Health Biomedical
Imaging Technology (BMIT) Study Section in 2010.
152
Cancer Prevention and Control Program
Nancy Cox, PhD, professor of medicine, was elected to a 4-year term in 2011 as a member-atlarge on the Section on Biological Sciences for the American Association for the Advancement of
Science (AAAS).
Selected Awards and Honors
Kenji Suzuki, PhD, assistant professor of radiology, was appointed deputy editor for Academic
Radiology in 2011, the Association of University Radiologists’ peer-reviewed journal. Dr. Suzuki
was also appointed in 2011 to the editorial board for Chest Disease Reports, a new, peer-reviewed
international medical journal reporting on the diagnosis and treatment of chest-related diseases.
William Dale, MD, PhD, associate professor of medicine, chief of the section of geriatrics,
and associate director of the MD/PhD Program in Medicine, Social Sciences, and Humanities
(MeSH), was elected by the International Society of Geriatric Oncology in 2010 to serve on the
editorial board of the Journal of Geriatric Oncology as a founding member.
Nora Jaskowiak, MD, associate professor of surgery, received the Favorite Faculty Award
from The University of Chicago Pritzker School of Medicine Class of 2011 in recognition of her
commitment to medical education.
David Meltzer, MD, PhD, professor of medicine, was selected in 2011 for a methodology
committee to assist the Patient Centered Outcomes Research Institute, a national nonprofit, with
building a consensus on methodologies for binding researchers to a common approach in furnishing comparative effectiveness data.
Olufunmilayo Olopade, MBBS, the Walter L. Palmer Professor of Medicine and Human
Genetics, associate dean for global health, and director of The University of Chicago Center for
Clinical Cancer Genetics, was elected to the American Academy of Arts & Sciences (AAAS) in
2010. Dr. Olopade was also elected to the board of directors for the American Board of Internal
Medicine (ABIM), received an honorary doctoral degree from Princeton University for her efforts
in breast cancer research and treatment, and received the Distinguished Service Award from the
American Cancer Society (ACS) in 2010. In 2011, Dr. Olopade was appointed by President Barack
Obama to serve on the National Cancer Advisory Board (NCAB), the highest level board that
oversees the activities of the National Cancer Institute (NCI). Dr. Olopade was also elected to the
American Philosophical Society and named a “Women Deliver 100” honoree, which recognizes
100 individuals committed to improving the lives of girls and women around the world.
UCCCC SCIENTIFIC REPORT 2010 – 2011
Karen E. Kim, MD, MS, associate professor of medicine, was named director of the UCCCC’s
Office of Community Engagement and Cancer Disparities (OCECD) in 2010 to oversee efforts in
building partnerships with local communities to enhance healthcare. Dr. Kim was also appointed
by the National Institutes of Health to serve on the Health Advisory Committee on Research on
Women’s Health in 2010 to address scientific, legal, and ethical issues affecting the health of our
nation’s women through biomedical and behavioral research and related cancer opportunities.
153
Integrated Research Initiatives
Integrated Research Initiatives
The UCCCC emphasizes collaboration among its members from a
broad range of disciplines to elucidate the determinants of cancer,
implement new approaches to screening and prevention, and
develop new diagnostics and personalized therapeutics to detect
and control cancer. The UCCCC stimulates interdisciplinary collaborations through several integrated research initiatives including
the Specialized Program of Research Excellence in Breast Cancer,
Leukemia and Lymphoma Society Specialized Center of Research,
Institute for Genomics and Systems Biology, Ludwig Center for
Metastasis Research, Systems Biology Approach for the Study
of Therapy-Related Acute Myeloid Leukemia, and Center for
UCCCC SCIENTIFIC REPORT 2010 – 2011 Personalized Therapeutics.
Specialized Program of Research Excellence (SPORE)
in Breast Cancer
PRINCIPAL INVESTIGATOR: OLUFUNMILAYO OLOPADE, MBBS
CO-PRINCIPAL INVESTIGATORS: GINI FLEMING, MD, AND MARYELLEN GIGER, PHD
The University of Chicago Breast Cancer SPORE brings together a multidisciplinary team of
basic, clinical, and population science investigators to perform innovative research using a global
strategy to reduce suffering from breast cancer. Awarded by the National Cancer Institute (NCI),
the program is one of only 11 Breast SPOREs in the United States. The University of Chicago
Breast SPORE aims to translate recent genetic and imaging advances to benefit women who are at
increased risk of developing an aggressive form of breast cancer, which disproportionately affects
young African American women.
The UCCCC integrates researchers from its Pharmacogenomics and Experimental Therapeutics,
Advanced Imaging, and Cancer Prevention and Control Programs. Basic researchers in genetics,
bioinformatics, molecular biology, biophysics, and structural biology collaborate with clinical
researchers specializing in epidemiology, medical oncology, surgical oncology, and radiation
oncology to facilitate the translation of scientific advances to patients.
The SPORE comprises four translational research projects, each co-led by basic and applied investigators from the UCCCC. These projects aim to 1) develop mammography and MR image-based
markers for assessing breast density to quantify breast cancer risk and monitor therapeutic response;
2) determine whether MR imaging with improved spectral, temporal, and spatial sampling leads
to improved detection of early breast cancer; 3) evaluate whether variations in genes involved in
hormone and xenobiotic metabolism influence breast cancer risk; and 4) identify population-specific
genetic variants that influence toxicity to breast cancer chemotherapy. These projects are supported
by core facilities in Analytic and Informatics; Biospecimen, Pathology and Genotyping; and Administration, each built on the unique strengths of existing UCCCC shared resources.
154
PRINCIPAL INVESTIGATOR: MICHAEL THIRMAN, MD
The SCOR, a multidisciplinary initiative awarded by the Leukemia and Lymphoma Society
of America, is an integrated program aimed at developing cell-permeable peptides and small
molecules as novel therapeutics for hematologic malignancies. The program comprises a highly
interactive group of chemists, molecular biologists, and clinicians who might not otherwise have
the opportunity to work together in a translational research program in leukemia and lymphoma.
The SCOR represents a collaborative effort among three institutions, involving 11 University of
Chicago senior researchers as well as two project leaders from an NCI-designated Cancer Center
at the University of California, San Diego (UCSD), and from Cornell University (CU).
Institute for Genomics and Systems Biology (IGSB)
DIRECTOR: KEVIN WHITE, PHD
The IGSB represents a collaborative effort between The University of Chicago and Argonne
National Laboratory (ANL) to advance technology development for genome analysis and accelerate
the transition of basic discoveries in genome science to translational and clinical research. Research
focuses on genomics and systems biology approaches to understand genome function evolution,
uncover new diagnostic and therapeutic targets, and discover new strategies for complex human
diseases with a major focus on cancer. The IGSB promotes 10 areas of investigation, including
proteomics and structural genomics, computational biology and informatics, microbial systems
biology, evolutionary genomics and systems, biological engineering and technology development,
cellular and genomic networks, chemical genomics, cancer, population genomics and complex
diseases, and clinical genomics.
UCCCC SCIENTIFIC REPORT 2010 – 2011
Efforts are focused on developing a common therapeutic strategy based on the targeting of proteinprotein interactions in leukemia and lymphoma, rather than focusing on a single disease entity.
SCOR projects center on 1) targeting transducible anticancer peptide therapeutics to kill tumor
cells in vivo (UCSD); 2) developing peptide and small molecule therapeutics for MLL-associated
leukemia (UCCCC); and 3) developing anti-BCL-6 targeted therapy for B-cell lymphomas
(CU). Six associated cores, including Peptide Therapeutics, Small Molecule Therapeutics, Patient
Demographics and Cell Bank, Hematopathology, Clinical Trials and Minimal Residual Disease
Monitoring, Hematopathology, Clinical Trials and Minimal Residual Disease Monitoring, and
Stem Cell Processing and Purging provide valuable reagents and expertise for each of the projects.
Integrated Research Initiatives
Leukemia and Lymphoma Society Specialized Center of
Research (SCOR)
More than 70 IGSB investigators from ANL and over 20 departments in the Biological Sciences
and Physical Sciences Divisions at The University of Chicago are performing research on complex
biological systems using a variety of experimental, computational, and theoretical approaches.
Current research initiatives include 1) the 1000 Chicago Cancer Genome Project, a joint effort
with The University of Chicago Medical Center to sequence the transcriptomes of 1000 tumors
to identify new therapeutic targets; 2) discovery of genomic variation and expression patterns in
metabolic diseases and diabetes for evaluating drug therapy outcomes; and 3) determination of the
relationship between bacteria and inflammatory bowel disease.
155
Integrated Research Initiatives
The IGSB features four core facilities to support its research, including the Cellular Screening
Center (CSC) for high-throughput RNAi and chemical compound screening, the High-Throughput Genome Analysis Core (HGAC) for ultra-high-throughput sequencing and microarray
processing, the Micro-Western Array Core (MWAC) for quantitative protein studies, and the
BAC-Recombineering Core (BRC) for imaging and measuring spatiotemporal expression of
fluorescently tagged proteins in model organisms.
Ludwig Center for Metastasis Research
UCCCC SCIENTIFIC REPORT 2010 – 2011 CO-DIRECTORS: RALPH WEICHSELBAUM, MD, AND GEOFFREY GREENE, PHD
156
The Ludwig Center for Metastasis Research aims to improve our understanding of metastasis
and translate laboratory concepts into novel therapeutics for the prevention and treatment of
metastasis. The Center, established in 2006 by an endowment from the Ludwig Fund, is closely
affiliated with the UCCCC and fosters collaborations among researchers from various disciplines,
including molecular and cell biology, bioinformatics, chemistry, genetics, imaging, and medicine.
Investigators are initially targeting metastasis of breast and prostate cancers by developing radiolabeled steroid receptor modulators and novel receptor-targeted nanoscale reagents to selectively
image and treat tumors expressing estrogen or androgen receptors. Researchers are also identifying small molecule reagents for the sensitization of tumors to ionizing radiation or chemotherapy.
Systems Biology Approach for the Study of Therapy-Related
Acute Myeloid Leukemia (t-AML)
PRINCIPAL INVESTIGATOR: MICHELLE LE BEAU, PHD
Supported by generous funding from the Cancer Research Foundation (CRF) since 2009, The
University of Chicago is employing a multidisciplinary systems biology and genomics approach
to study t-AML. Therapy-related acute myeloid leukemia, which affects approximately 8%-10%
of all patients treated for cancer, is a direct result of mutational events that are induced by chemotherapy or radiotherapy used in the treatment of primary malignancies. Patients who have
received immunosuppressive agents for organ transplantation and the elderly are also at risk for
developing t-AML and AML. An interdisciplinary team of scientists, representing the UCCCC
and the IGSB, is using a comprehensive approach to identify individuals at risk for developing
t-AML, identify genetic susceptibility factors that are involved, and design effective prevention and
treatment strategies for this disease. The team has extensive research expertise in clinical oncology,
hematopathology, genetics, genomics, systems biology, computational modeling of molecular
networks, and hematopoiesis. Using a systems approach, these investigators are integrating six
research projects involving high-throughput screening, stem cell biology, pharmacogenetics,
clinical trial design, and computation to understand the basic biology of t-AML. Taken together,
these projects are furthering our understanding of the molecular basis of the disease and will lead
to improved therapies, earlier detection, and prevention strategies.
PRINCIPAL INVESTIGATOR: MARK RATAIN, MD
The UCCCC’s newly established Center for Personalized Therapeutics is developing individualized prevention and treatment strategies for cancer based on genetic, social, environmental, and
behavioral factors. The Center, which combines the expertise of basic and clinical researchers
in pharmacogenomics, is focusing its efforts on the 1200 Patients Project, a clinical study that
incorporates broad genetic information into routine clinical practice to guide medical treatment
decisions. This information will help clinicians predict which patients will respond favorably to
specific medications, experience severe side effects from certain therapies, or respond positively to
higher drug dosing. The Center facilitates collaborations among researchers who are performing
genome-wide discovery and clinical validation of pharmacogenomic markers for chemotherapy,
developing tools for improved analysis of therapeutic response, and developing targeted therapies.
These efforts are facilitating the development of a new medical system that emphasizes personalized medical care.
Integrated Research Initiatives
Center for Personalized Therapeutics
UCCCC SCIENTIFIC REPORT 2010 – 2011
157
158
Cancer Registry
patients diagnosed or treated at The University of Chicago Medical
Center (UCMC). Vital statistics, including patient demographics,
tumor site and histology, stage of disease, treatment, and outcomes
Cancer Registry
Since the 1920s, the UCCCC Cancer Registry has documented all
for each case are collected and reported to national cancer surveillance programs. The data are also essential for epidemiologic
and health disparity grant applications, cancer program planning,
and other cancer research initiatives.
2010 Cancer Cases by Site
NEWLY
DIAGNOSED
RECURRENT/
PROGRESSIVE
DISEASE
TOTAL
% OF TOTAL
CASES
DIGESTIVE SYSTEM
563
65
628
18.5%
MALE GENITAL SYSTEM
496
72
568
16.8%
BREAST
308
38
346
10.2%
RESPIRATORY SYSTEM
286
47
333
9.8%
URINARY SYSTEM
242
42
284
8.4%
ENDOCRINE SYSTEM
173
25
198
5.8%
FEMALE GENITAL SYSTEM
149
28
177
5.2%
ORAL CAVITY & PHARYNX
127
34
161
4.7%
PRIMARY SITE
LYMPHOMA
112
26
138
4.1%
BRAIN & OTHER NERVOUS SYSTEM
99
20
119
3.5%
LEUKEMIA
97
28
125
3.7%
MISCELLANEOUS
59
10
69
2.0%
SKIN EXCLUDING BASAL & SQUAMOUS
49
19
68
2.0%
MYELOMA
43
5
48
1.4%
SOFT TISSUE
40
12
52
1.5%
MESOTHELIOMA
40
7
47
1.4%
BONES & JOINTS
21
3
24
0.7%
KAPOSI SARCOMA
3
0
3
0.1%
EYE & ORBIT
TOTAL
1
2
3
0.1%
2,908
483
3,391
100%
UCCCC SCIENTIFIC REPORT 2010 – 2011
In 2010, a total of 3,391 patients were diagnosed and/or treated for cancer at the UCMC. Of
these patients, 2,908 (85.8%) were new diagnoses and 483 (14.2%) were initially treated elsewhere
and referred to the UCMC for recurrent or progressive disease. The most frequent primary sites
diagnosed and/or treated for cancer include the digestive system, male genital system, breast,
respiratory system, and urinary system.
159
Financials
Financials
The University of Chicago Comprehensive Cancer Center
Reporting Date: 7/31/11
SUM OF
DIRECT COSTS
SUM OF TOTAL COSTS
(DIRECT + INDIRECT)
ACS
$1,050,166
1,190,000
NCI
$24,512,845
$34,060,007
FUNDING AGENCY
NSF
$178,398
$256,044
OTHER NIH
$38,741,794
$53,051,976
OTHER PEER-REVIEWED
$5,524,377
$7,430,788
$70,025,580
$95,988,815
INDUSTRY
$6,688,233
$8,734,630
OTHER NON-PEER REVIEWED
$7,335,483
$7,779,197
SUBTOTAL OF NON-PEER REVIEWED
$14,023,716
$16,513,827
$84,049,296
$112,502,642
UCCCC SCIENTIFIC REPORT 2010 – 2011 SUBTOTAL OF PEER-REVIEWED
160
GRAND TOTAL (ALL PROJECTS)
EXECUTIVE EDITOR
Hoyee Leong, PhD
Director for Scientific Communications and Strategic Partnerships
GRAPHIC DESIGN
Rogue Element Inc.
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For more information about the UCCCC:
Connect by phone at 1-773-702-6180 (UCCCC Administrative Office)
Make an appointment at 1-855-702-8222 (adults) or 1-773-702-6808 (pediatrics)
Visit us online at cancer.uchicago.edu
The University of Chicago
Comprehensive Cancer Center
5841 S. Maryland Ave., MC1140 H212
Chicago, IL 60637
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