Congress Highlights
Moving beyond the single agent
targeting of activated pathways in
cancer and emerging therapeutic
targets in rare cancers
Jacques De Grève, PD, PhD
Oncologisch Centrum UZ Brussel
The ECC meeting is mostly focused on clinical results and some translational medicine. Nevertheless a
couple of interesting developmental topics were presented.
Identification of primary drivers in all cancer types is moving along and treatments that match these
genotypes are available or in development. One of the next challenges is to increase the initial efficacy of
these treatments and overcoming secondary resistance. Indeed, all cancers treated with targeted agents,
despite impressive results, ultimately become resistant due to secondary resistance mechanisms. In
addition there is also something as “innate” resistance: the primary treatments do not achieve a maximal
pathway shutdown and therapeutic efficacy. This is in part due to the pharmacological limitations of small
molecules and monoclonal antibodies in the inhibition of the pathways they target. Hitting the same target
with specific siRNA’s is generally more effective in shutting down the activated pathway. In addition, this
innate resistance is also due to functional responsiveness of the cells that results in the activation of
alternative pathways that dampen the effect of the primary treatment. Identification of these functional
resistance mechanisms is important, as they would be candidate co-targets for primary targeted therapies.
Another major void in our cancer armamentarium is the therapeutic exploitation of recessive cancer genes
and tumor suppressor genes.
(Belg J Med Oncol 2015;9:260-62)
EGFR
Mutant EGFR targeting in lung cancer can result in the
functional activation of the MET pathway. This is innate resistance. Inhibition of MET could then synergize with concomitant EGFR targeting. When this becomes constitutive, for example due to amplification of
the MET gene, then we speak of a secondary resistance
mechanism. The same applies to the newer third generation EGFR inhibitors that have activity against the
second site T790M mutation that generates resistance
to the first-generation EGFR inhibitors. These third
generation EGFR inhibitors also generate specific resistance mechanisms including the appearance of cell
clones without the T790M mutation and new second
site mutations that create new steric hindrance to the
third generation TKI. Third generation TKIs have variable activity against EGFR with only a primary mutation and some have no significant activity against the
wild-type EGFR leading to decreased skin toxicity.
Three drugs (AZD9291, CO1686 and WZ4002) are
currently in advanced clinical development.
Please send all correspondence to: Prof J. De Grève. MD, PhD, Oncologisch Centrum UZ Brussel, Laarbeeklaan 101, 1090 Jette, Belgium,
Tel: +32 (0)2 4776415, E-mail: [email protected].
Conflict of interest: the author has nothing to declare and indicates no potential conflict of interest.
Keywords: EGFR, resistance, T790M, WZ4002, AZD9291, CO1686, BRAF, MET, AXL, FGFR, Malignant rhabdoid tumor, INI1, Epitheloid
sarcoma, HDM2, pimasertib.
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Volume 9, Special Edition, November 2015
Lee et al. studied resistance to WZ4002 in a lung cancer cell line.1 Through a multi-kinase bypass assay they
identified the IGF1R pathway as a mechanism of resistance and provide preclinical evidence that down-regulation of IGF1R with a small molecule AG1024 results in sensitization to the EGFR inhibitor. They
propose combined IGF1R and EGFR inhibition. It
should be noted that many inhibitors (monoclonal antibodies and small molecules) of the IGF1R pathway
have been investigated in the clinic, including in lung
cancer, and have massively failed as single agents. The
problem is that the IGF1R pathway is not constitutively
activated (except in Ewing sarcoma) and therefore not
a proper target in itself. Perhaps these drugs could have
a future in combinatorial strategies provided the combination is tolerable and more effective in patients. This
could advance not only the treatment of resistance but
also might overcome baseline innate resistance to targeted therapies, in this case mutant EGFR.
BRAF
Inhibition of mutant BRAF is clinically relevant as
shown in melanoma and lung cancer carrying V600
mutations. In addition, the combination with downstream inhibitors of MEK or ERK has been respectively
clinically and pre-clinically validated. Non-V6900
BRAF mutations that are often found in other cancers
such as lung cancer have not been therapeutically explored in the clinic so far.
One of the problems of BRAF inhibition is the role of
c-RAF that can be paradoxically activated when BRAF
is targeted, stimulate the MEK-ERK pathway and thus
create resistance to BRAF inhibition. This occurs particularly when BRAF has a kinase–impaired mutation
or when BRAF is wild-type. Pan-RAF inhibitors have
therefore been developed. Rasco et al. investigated a
novel pan-RAF inhibitor (MLN2480, Millennium)
and there is some promise that they could overcome
the paradoxical role of c-RAF. These inhibitors might
also become relevant for the non-V600 mutations some
of which are kinase-impaired (for example in lung cancer) and respond less well or not to current BRAF
inhibitors.2
MET, AXL and FGFR
Dysregulation of the MET, AXL and FGFR kinases has
been implicated in tumor progression and metastasis
formation. These three targets can be separately activated in many cancer types, either as part of the original cancer pathogenesis or as a mechanism of
Belgian Journal of Medical Oncology
secondary resistance to inhibition of another pathway;
for example amplification of MET after inhibition of the
EGFR pathway. MET can be activated in various ways
(growth factor overexpression, amplification, mutation). S49076 (Servier) is a small molecule targeting
these three kinases. Preclinical data suggest a good
safety profile.3 Toxicity includes peripheral edema, hypo-albuminemia, yellow skin pigmentation, dysesthesia and asthenia. One might wonder about the positioning and clinical utility of multi-targeting drugs as
multi-targeting also generates more toxicity. These targets are normally not co-activated in a particular cancer. Thus, patients are exposed to needless additional
mechanism-based toxicities due to the targeting of kinases that are irrelevant for their cancer.
INI1
Malignant rhabdoid tumor (MRT) of the kidney is
characterized by early local and distant metastases and
resistance to chemotherapy. The survival rate for renal
malignant rhabdoid tumors is only 20-25%. Malignant
rhabdoid tumors also occur in practically every location in the body, including the brain, liver, soft tissues,
lung, skin, and heart. These tumors frequently contain
deletions at chromosome locus 22q11.1 including a locus that contains the SWI/SNF related, matrix-associated, actin-dependent regulator of chromatin, subfamily B, member 1 (SMARCB1) gene, also known as
integrase interactor 1 (INI1) and many other synonyms. SMARCB1 encodes a member of the human
SWI/SNF complex. Combined FISH, sequencing,
high-density single nucleotide polymorphism–based
oligonucleotide arrays, and multiplex ligation-dependent probe amplification enable the identification of biallelic, inactivation of SMARCB1 in nearly all malignant rhabdoid tumors, consistent with the two-hit
model. Thus, SMARCB1 is a classic recessive cancer
gene and the primary gene responsible for malignant
rhabdoid tumor pathogenesis. The mechanism by
which SMARCB1 perturbation leads to aggressive malignancies relates to its role in epigenetic modification.
The SWI/SNF complex acts in the remodeling of chromatin, which regulates gene transcription and DNA
repair. Despite an aggressive clinical behavior, malignant rhabdoid tumors are generally diploid and genomically stable, a characteristic that predicts potential
high efficiency of targeted therapies. Tumor development in SMARCB1-deficient mice is greatly accelerated
in the absence of functional p53 protein. This suggests
cooperation between SMARCB1 and the pRB, CyclinD1,
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6
Congress Highlights
and p53 pathways. Epitheloid sarcoma (ES) is a rare
soft tissue sarcoma characterized by epitheloid-like features. It accounts for less than 1% of all soft tissue sarcomas and usually occurs in (distal) limbs, more rarely
in the trunk. Epitheloid sarcoma is usually diagnosed
in young adults, but can occur at any age. It has a high
rate of relapse after initial treatment, recurs locally and
has a five-year survival rate between 25 and 78%. Mutations in INI1 can also be found in this cancer and in
other rare cancers such as renal medullary carcinomas,
some epitheloid malignant peripheral nerve sheath tumors, myo-epithelial carcinomas and extra-skeletal
myxoid chondrosarcomas. Inactivation of INI1 abrogates SWI/SNF activity and, in preclinical models,
confers sensitivity to EPZ-6438. EPZ-6438 is a small
molecule inhibitor of EZH2, the catalytic subunit of
Polycomb Repressive Complex 2 (PRC2) responsible
for methylation of H3K27. Aberrant EZH2 activity has
also been implicated as an oncogenic driver of a number of human cancers, including non-Hodgkin lymphoma (NHL). The SWI/SNF complex acts in opposition to the PRC2. EPZ-6438 is therefore expected to be
potentially active against gain of function of PRC2 as
well as in loss of function of SWI/SNF. Italiano et al.
reported on the initial clinical experience with EPZ6438 (E7438) (Enhancer of Zeste-Homolog 2 (EZH2)
inhibitor, Eisai and Epizyme).4 They selected patients
with INI1-negative tumors. Promising clinical activity
was found in MRT and ES patients with a favorable
toxicity profile. Further development in INI1-negative
tumors is planned. This is a very interesting development as it may forebode the therapeutic exploitation of
recessive cancer genes, a huge challenge. This model
could have a high impact for all cancers and especially
in cancers that have mutations in chromatin remodeling genes (for example ovarian cancer). It is currently
the second example directly exploiting recessive cancer
genes, after olaparib.
is the p53 tumor suppressor. Hdm2 achieves this repression by binding to and blocking the N-terminal
trans-activation domain of p53. Hdm2 inhibition can
thus restore p53 function. In addition MAPK pathway
inhibition has strong synergy with Hdm2 inhibition.
De Weger et al. reported on a phase 1 study in patients
with an activated MAPK pathway combining an Hdm2
antagonist SAR405838 (Sanofi) with the MEK inhibitor pimasertib (Sanofi and Merck).5 Patient selection
was based on RAS mutation-p53wt status. Toxicity
wasimportant and included thrombocytopenia (main
DLT), fatigue, pneumonitis, amylase/lipase increase,
acneiform dermatitis and pustular rash, asymptomatic
LVEF drop and palmar-plantar erythrodysplasia, diarrhea, serious retinal detachment that may involve the
macula, nausea, vomiting and peripheral edema. Clinical benefit including one long lasting PR was observed
in endometrial cancer, NSCLC, cholangiocarcinoma
and CRC. There was no PK interaction between the
two drugs. Despite this clinical activity, further safety
evaluations are needed.
Conclusion
Prudent headway is being made in enhancing the efficacy of targeted therapies and perhaps the dawn of
therapeutic exploitation of recessive cancer genes has
arrived.
References
1. Lee J, Park S, Rho J et al. Combined inhibition of IGF1R and EGFR signaling
overcomes the resistance to 3rd-generation EGFR kinase inhibitors caused by
IGF1R activation. Presented at ECC 2015; Abstract #101.
2. Rasco D, Middleton M, Gonzalez R et al. Phase I study of two dosing schedules of the investigational oral pan-RAF kinase inhibitor MLN2480 in patients
(pts) with advanced solid tumors or melanoma. Presented at ECC 2015; Abstract #300.
3. Azaro A, Rodon J, Herranz M et al. First-in-human phase I dose-escalation
study of a MET/AXL/FGFR inhibitor, S 49076, in patients with advanced solid
tumors. Presented at ECC 2015; Abstract #301.
HDM2
Hdm2 is the human homolog of the murine double
minute (mdm2) oncogene, which codes for the Mdm2
protein. Several human cancers have increased levels of
Hdm2, including soft tissue sarcomas and osteosarcomas as well as breast cancers. The key target of Hdm2
Belgian Journal of Medical Oncology
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4. Italiano A, Keilhack H, Toulmonde M et al. A phase 1 study of EPZ-6438
(E7438), an Enhancer of Zeste-Homolog 2 (EZH2) inhibitor: Preliminary activity in
INI1-negative tumors. Presented at ECC 2015; Abstract #302.
5. De Weger V, Varga A, De Jonge M et al. A phase I study of the HDM2 antagonist SAR405838 combined with the MEK inhibitor pimasertib in patients
with advanced solid tumors. Presented at ECC 2015; Abstract #303.
Volume 9, Special Edition, November 2015