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molecular answers and targets
on the horizon for the treatment
of genitourinary malignancies
50IN GENES, CHROMOSOMES AND THE TREATMENT
OF BLADDER CANCER
J.E. Rosenberg
Genitourinary Oncology Service, Memorial Sloan-Kettering Cancer Center,
New York, NY, UNITED STATES OF AMERICA
Molecular analysis of bladder cancer is transforming our understanding of this
disease. The relative abundance of bladder tumor tissue from these patients due to
frequent resections provides a major opportunity to understand the molecular
pathogenesis. Non-muscle invasive bladder cancer tends to be characterized by
oncogenic activation events (FGFR3 mutation, PIK3CA mutation), while muscle
invasive bladder cancer is more associated with tumor suppressor gene inactivation
(p53, Rb). DNA copy number analysis identifies multiple regions of recurrent
chromosomal gains and losses, many of which delineate known oncogenes and
tumor suppressor genes. High-throughput analysis of bladder cancer specimens is
identifying multiple new targets that may be therapeutically tractable in subsets of
patients, including Her2 overexpression and amplification, b-raf mutation, and TSC1
mutation. The clinical implications of the molecular events in bladder cancer have
yet to be identified. Large-scale genomic efforts linking clinical data to outcome
should lead to an improved understand of the molecular landscape of bladder cancer.
Next-generation sequencing technologies are allowing the rapid assessment of
molecular alterations, which may lead to clinical trials enriched for patients whose
tumors contain druggable alterations. To capitalize on the genomic knowledge
gained in bladder cancer, reliable molecular tests that are accepted by regulatory
authorities, along with targeted agents aimed at actionable alterations are, need to
break out of the current therapeutic stalemate. Trials targeting some of these novel
alterations are beginning to enroll patients.
Disclosure: J.E. Rosenberg: 1. Imclone- research funding 2. Oncogenex- consulting
3. Boehringer-Ingelheim- consulting 4. GSK- research funding 5. Novartis- research
funding
51IN GENOMICS IN RENAL CANCER: FROM SCIENCE
TO CLINICAL PRACTICE
B.T. Teh
Director and Principal Investigator, Nccs-vari Translational Research Laboratory,
National Cancer Centre Singapore, Singapore, SINGAPORE
Approximately 290,000 new cases of renal cell carcinoma (RCC) are diagnosed each
year worldwide and 102,000 deaths. It is a morphologically, and genetically
heterogenous disease with distinct underlying molecular mechanisms in each
subtype. In this lecture, the evidence of this molecular heterogeneity with more
recent discoveries will be presented and discussed. For example, we have recently
identified the frequent mutations of PBRM1, a member of the SWI-SNF complex, in
clear cell RCC (the most common type of RCC) and a lesser degree of mutations in
a group of histone modifiers. This has opened up a new field of investigations, from
basic biology to clinical implications. In addition, we also demonstrated the
involvement of LRRK2, a gene associated with early-onset Parkinson’s disease, in
papillary type 1 RCC (second most common type of RCC) and its interaction with
c-MET, a gene that has been previously implied in this subtype of tumors. We have
also recently discovered a novel metabolic pathway that is integral to the
tumorigenesis of papillary type II (an aggressive type of papillary tumor). All these
present new opportunities for further investigations to establish their biological and
therapeutic roles in RCC.
Disclosure: The author has declared no conflicts of interest.
Annals of Oncology 23 (Supplement 9): ix39, 2012
doi:10.1093/annonc/mds379
52IN SIGNALING PATHWAYS, MECHANISMS OF RESISTANCE
AND TREATMENT DECISIONS IN RENAL CELL CANCER
G. Tortora
Medical Oncology, University of Verona Policlinico Borgo Roma, Verona, ITALY
Renal cell cancer (RCC) is a highly vascularised disease and angiogenesis plays a
critical role in tumor growth and spreading. For this reason, the main angiogenic
pathways, involving the Vascular endothelial growth factors (VEGFs), the VEGF
receptors (VEGF-Rs), and the mammalian target of rapamycin (mTOR) are the
targets of drugs that have dramatically improved the outcome of patients affected by
this disease. An increasing number of active agents directed against the above targets
and other angiogenesis-related proteins, including the Fibroblast growth factors
(FGFs) and their receptors (FGF-Rs), is now available. However, a biologically-based
therapeutic algorithm is still missing and the onset of drug resistance and the lack of
validated biomarkers predictive of response to single agents and, more in general, to
antiangiogenic drugs, do not allow to take full advantage of the therapeutic options
available. Interlukin 8 (IL-8) and FGF seem to play a role in the induction of
resistance to TKIs. IL-8 overexpression is associated to resistance to sunitinib and
IL-8 gene polymorphisms correlate with survival in patients treated with pazopanib.
Increases in the FGF/FGF-Rs signalling is observed as escape to inhibition of the
VEGF-Rs by TKIs. On the other hand, activation of the PI3K/Akt pathway is
responsible for the onset of resistance to mTOR inhibitors. Several studies are now
extensively analyzing the predictive value of a variety of angiogenesis-related
biomarkers, including soluble VEGF and VEGF-Rs, IL-8 expression and secretion,
polymorphisms of VEGF and IL-8 genes, and VHL mutations. In addition imaging
techniques are also under evaluation as promising dynamic biomarkers of
antiangiogenic drugs activity or resistance in RCC. A better understanding of the
mechanisms of resistance and the validation of reliable biomarkers predictive of drug
activity or resistance will help to select patients who can benefit from current and
future treatments.
Disclosure: The author has declared no conflicts of interest.
53IN MOLECULAR INSIGHTS AND TREATMENT OUTLOOK
FOR GU MALIGNANCIES
J. Bellmunt
Medical Oncology, University Hospital del Mar-IMIM, Barcelona, SPAIN
The use of targeted therapies has significantly improved outcomes for patients with
mRCC. At present, in Europe and/or the USA, six/seven targeted agents are
approved for first- and second-line treatment of clear cell mRCC: sunitinib,
sorafenib, temsirolimus, everolimus, bevacizumab (in combination with interferon)
pazopanib and axitinib (in the US). In addition, several new targeted agents, such as
axitinib (in EU) and tivozanib, are also currently being filed for the treatment of
mRCC after successful results of the phase III trials .New treatment options include
targeting new pathways like c-MET or the use of novel more selective
inmunotherapies such as the anti-PD1 agent. The novel chemotherapeutic agent
Cabazitaxel with activity for CRPC in patients failing docetaxel is now available
filling an unmet medical need for these patients.In addition immunotherapy with
sipuleucel-T, the androgen biosynthesis inhibitor abiraterone acetate, the radioisotope
alpharadin and the anti-androgen MDV3100 have all shown to improve overall
survival in randomized phase III studies for patients with mCRPC. Agents such as
the dual VEGFr/MET inhibitor cabozantinib, the clusterin inhibitor custirsen and the
Src inhibitor dasatinib have shown encouraging results in phase II studies, and phase
III results with theses agents are eagerly awaited.Novel immunotherapeutics such as
prostate-specific membrane antigen-directed therapy and the anti-cytotoxic T
lymphocyte-associated receptor 4 (CTLA4) antibody ipilimumab are also under
investigation. Targeted therapy with novel drugs directed at specific molecular
pathways opens promising new avenues in urothelial tumors to improve patient
outcome. Several phase II/III trials, with focus on bevacizumab, aflibercept, sunitinib,
sorafenib, gefitinib, lapatinib and trastuzumab have not clarified any specific role for
these therapies. However, the presently accruing trial comparing CG +/bevazicumab
is in its half way to shed light on the role of antiangiogenics in
urothelial tumors. Other novel, promising targeted agents, including pazopanib,
cetuximab and everolimus has shown limited benefit. Identifying pathways critical
for tumorigenesis can provide potential strategies for therapeutic intervention in
specific tumor types.
Disclosure: The author has declared no conflicts of interest.
© European Society for Medical Oncology 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
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