Experimental Cancer Medicine Centres
in the United Kingdom
–
A Framework for Translating the Results of
Basic Science into Patient Benefit
Professor Herbie Newell and Dr Mags Sara -16 June 2007
Translational Research
“The exploitation of basic
research for patient benefit”
The Iterative Translational Research Cycle
Patient - Bed
Samples for
drug target
identification
and biomarker
development
New:
- Preventives
- Treatments
- Biomarkers
- Imaging
techniques
Results from
clinical trials
Laboratory - Bench
Translational Research – State-of-the-Art
Translational research offers a holistic approach to cancer
management in which laboratory studies are used to
optimize the prevention, detection and treatment of
cancer, e.g.:
– Identification of at-risk individuals and targets for
chemoprevention
– Development of improved diagnostic and prognostic biomarkers,
in particular those where the link to cancer pathology is
understood
– Discovery and therapeutic exploitation of targets linked to the
molecular pathology of cancer
– Facilitation of mechanistic early-phase trials of targeted
therapies
– Evaluation of genomic, proteomic, metabolomic biomarker and
molecular imaging methodologies that allow personalised
medicine
Translational Research Vision Cancer Management in 20??
• Genetic analysis at birth to predict life-time risk
• Lifestyle advice, and possibly chemoprevention,
to minimise risk
• Screening using metabolomic, proteomic or
genomic techniques, with imaging, to facilitate
early detection and accurate diagnosis
• If cancer is detected, surgery and/or targeted
chemo/radio therapy, with extensive use of
prognostic and predictive biomarkers, and
imaging technologies, to facilitate curative
personalised medicine
Key Objectives in Translational Research
• Drug Discovery and Development
– Well established in both academic and Pharma/Biotech
– Recent advances in cancer biology are providing a rich source of
new targets for exploitation
– New technologies in cancer drug discovery have the potential to
greatly accelerate both drug discovery and development
• Biomarker Identification and Qualification
–
–
–
–
Not historically a strength of Pharma/Biotech
Benefits from strong academic input
Well characterized populations and tissue collections essential
Generally introduced at too late a stage into drug discovery and
development
• The Holy Grail – Fully integrated biomarker and drug
discovery and development
Cancer Research UK and Drug Development
Pre-clinical development and early Phase clinical trials
The New Agents Committee of Cancer Research UK has
taken OVER ONE HUNDRED new cancer treatments into
early Phase clinical trials (1980-2007)
Later stage clinical trials
Cancer Research UK is the major funder of late stage trials
and cancer clinical trials units in the UK
Interactions with Pharma and Biotech
Cancer Research UK has a world-class technology transfer
capability in Cancer Research Technology
Past Cancer Research UK Success in
Academic Drug Discovery
Walter Ross –
Chlorambucil
Melphalan
Busulphan
Ken Harrap and Tom Connors –
Carboplatin
Malcolm Stevens –
Temozolomide
Contemporary Drug Discovery
Compound
Collections
Target ID/validation High-throughput
Compound
Screening
Combinatorial chemistry
Medicinal chemistry
Structure-based design
Hit-to-lead
Development
Lead
Optimisation
Cellular Mechanism
of Action
In vivo Evaluation
Clinical
Evaluation
Target I.D.
& Production
Assay
Development
Pick a Library
START
Hit
Li
y
ar
br
?
Produced by P. Sweetnam
Classic
PK/Tox
Development
Candidate
In Vivo
In Vitro
Cell-based
Animal studies
assay
Functional
Functional
Research
PK/TOX
a
ck
Drug Discovery Edition
?
Pi
Monopoly
Lead
Optimization
Characterization
No Hits
Absorption, Distribution,
Go to Start
Metabolism, Elimination
Targeted Therapies – Science Fact
not Science Fiction
• Antiendocrine agents
• Growth factor and growth factor receptor
antagonists
– Trastuzumab, cetuximab, gefitinib, erlotonib, lapatinib,
sorafinib, sunitinib
• Second messenger or signal transduction
inhibitors
– Imatinib, sorafinib
• Regulators of gene expression
– All-trans retinoic acid
Single Agent Activity of Targeted
Therapies – Objective response rates
• Imatinib
– CML >90%, Glioma ≤10%, GIST ca. 50%
• Trastuzumab
– Breast cancer 10-30%, ovary <10%
• Gefitinib, Erlotinib
– NSLC 10-30%, SCCHN <10%
• All-trans retinoic acid
– Acute promyelocytic leukaemia >90%
• Sunitinib
– Renal ca. 40%
Potential Reasons for the Modest Activity
of Single Agent Targeted Therapies
• Lack of “addiction” to the target – Tumour cells utilise
multiple pathways for survival and growth
• Genetic instability – Tumour cells rapidly develop
drug-insensitivity: target mutation or amplification, upregulation of alternative pathways or resistance
mechanisms
• Failure to select potentially sensitive patients for
therapy
• Inherent pharmacology - Drugs targeted at oncogene
products inhibit tumour growth but do not cause
tumour regression
Solutions to the Modest Activity of
Molecular Therapies
• Rational Combination therapy – targeted and/or
cytotoxic
• “Multi-targeted” targeted agents
• Early intervention – chemoprevention
• Exploitation of host stromal targets
• Patient and population enrichment strategies Biomarkers
• Agents that directly promote cell death
Experimental Cancer Medicine Centre Network
 £35 million joint initiative between CR-UK and the Departments of Health in England,
Scotland, Northern Ireland and Wales to develop and expand a major network of
Centres over 5 years under the auspices of the National Cancer Research Institute
 Builds on successful elements of the Departments of Health-funded National
Translational Cancer Research Network (NTRAC)
 Aims to integrate laboratory and clinical patient-based research to speed up the
development of new therapies
 Provides funds for infrastructure costs for translational research, knowledge
sharing and resources to benefit cancer patients
 Underpins translational work to develop new anti-cancer drugs and biomarkers
 19 centres of excellence awarded ECMC status by and international review panel
 Funding started April 2007
Expertise in the ECMC Network - I
•
•
•
•
•
•
Belfast – Biomarkers, pharmacokinetics and pharmacodynamics
Birmingham – Immunotherapy, gene therapy and biomarkers
Cambridge – Biomarkers, imaging, informatics and genomics
Cardiff – Pathology, haematology and tissue resources
Edinburgh – Informatics, pharmacokinetics and pharmacodynamics
Glasgow – Pharmacokinetics and pharmacodynamics, gene
therapy
• Institute of Cancer Research - Biomarkers, imaging,
pharmacokinetics and pharmacodynamics
• Imperial College London - Imaging, gene therapy, drug resistance
• Kings College London – Genomics, imaging, cell and gene
therapy
Expertise in the ECMC Network - II
• Leeds – Biomarkers, proteomics, pharmacokinetics and
pharmacodynamics
• Leicester – Chemoprevention and antibody therapeutics
• Liverpool – Pharmacokinetics and pharmacodynamics, proteomics
• Manchester – Imaging, pharmacokinetics and pharmacodynamics,
immunotherapy
• Newcastle – Pharmacokinetics and pharmacodynamics, imaging
• Oxford – Angiogenesis and immunotherapy
• Sheffield – Bone oncology, vascular targeted therapies
• Southampton – Immunotherapy
• St Bartholomew's and the London School of Medicine – Gene
therapy, imaging and biomarkers
• University College London – Immunotherapy and antibody
targeted therapies, imaging, bioinformatics
Objectives of the ECMC Network

To expand the portfolio of experimental cancer medicine in
the UK

To provide a single focus for research charity, industry and
the Department of Health's experimental cancer medicine
activity

To make the UK an attractive location for industrysponsored experimental cancer medicine

To provide consumer engagement and involvement in
experimental cancer medicine, and to expedite the
introduction of new cancer medicines
Development of the ECMC Network - I
•
Establish a new model: A network for the community based on collaboration and
teamwork, a network of membership, no figure heads
•
Role of ECMC Secretariat:
 Support the network in its activities, and facilitate communication and
collaboration
 Manage and administer the finances of the Network and Secretariat (secretariat
budget)
 Support specific groups within experimental cancer medicine to develop best
practices and standardised shared resources:
• ECMC Bio-Analysis and Quality Assurance group
• ECMC Research Nurse group
• ECMC Data managers group
• ECMC Imaging group
Development of the ECMC Network - II
 Support for regular ECMC network meetings and ad hoc workshops
 Support biannual scientific fora:
 Early Clinical Trials Forum – 1st Meeting held December 2006
 Translational Research in Late Phase Trials Forum - 5 July 2007
• Theme: Biomarkers in Late Phase Clinical Trials
• Workshops: Genomics and proteomics in sample analysis, bio-banking
and tissue resources, biomarkers in development of EGFr/ErbB inhibitors
 Make available up-to-date information on open ECMC clinical trials on the
CancerHelp UK clinical trials database
 Working with consumer groups to promote consumer involvement in the
Network
 Develop branding/communication strategy
 Interface with other relevant committees, industry and external bodies
Conclusions
• Translational research offers the prospect of
significant advances in patient management
• The Experiment Cancer Medicine Centre
network provides the framework and
infrastructure support for translational cancer
research in the UK
• The ECMC is a key partnership between
government, cancer charities, industry and
consumers
Acknowledgements
• Dr Mags Sara and Ms Kate Etchells – ECMC
Secretariat
• National Cancer Research Institute – Dr Jane Cope
• Devolved Departments of Health
• Colleagues in the ECMC network
• CancerHelp UK
• Consumers