Renal Cell Carcinoma Ronald M. Bukowski (cid:129) Robert A. Figlin Robert J. Motzer Editors Renal Cell Carcinoma Molecular Targets and Clinical Applications Second Edition Editors Ronald M. Bukowski Robert J. Motzer Cleveland Clinic Foundation Memorial-Sloan Kettering Cancer Center Cleveland Clinic Taussig Cancer Center New York, NY and CCF Lerner College of Medicine of CWRU Cleveland, OH Robert A. Figlin Division of Medical Oncology & Experimental Therapeutics City of Hope National Medical Center/Beckman Research Institute Duarte, CA ISBN: 978-1-58829-737-2 e-ISBN: 978-1-59745-332-5 DOI: 10.1007/978-1-59745-332-5 Library of Congress Control Number: 2008940836 © Humana Press, a part of Springer Science+Business Media, LLC 2009 All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Humana Press, c/o Springer Science+Business Media, LLC, 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden. The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identifi ed as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights. Printed on acid-free paper springer.com Preface Ronald M. Bukowski, Robert J. Motzer, and Robert A. Figlin Renal cancer comprises 3% of all malignant tumors, with an estimated incidence of 39,000 new cases with 13,000 deaths in 2006 (1). A study comparing 43,685 cases of renal cancer from 1973–1985 with those diagnosed in 1986–1998 (SEER data- base) demonstrated a marginal increase in the proportion of localized cancers and a decrease in advanced cases in the latter group. During the next 10-year period, however, the increase in localized and smaller tumors appears real, but overall survival (OS) differences are not yet apparent (2). While increased imaging and laboratory testing may generally explain the increased incidence, other environ- mental factors may also play a role (2). Historically, patients presented with the classic triad of symptoms including flank pain, hematuria, and a palpable abdominal mass; but recently, increasing numbers of individuals are being diagnosed when asymptomatic with an inciden- tally discovered renal mass. Advances in imaging and techniques have increased the percent of patients who are eligible for surgical intervention, but a significant percent of patients still present with surgically unresectable disease (3) or will subsequently develop metastatic disease. Histology The importance of histology in predicting the biologic characteristics and clinical behavior of renal cancers was recognized in the last decade. Renal cell carcinoma (RCC) represents a group of histologic subtypes with unique morphologic and genetic characteristics (4). Clear-cell renal carcinoma is the most common type of renal cancer, accounting for ∼70–85% of renal epithelial malignancies, and arises from the proximal convo- luted tubule. Papillary renal cancer is the second most common type comprising 10–15% of renal tumors. Understanding histologic subtypes and associated gene alterations has provided the opportunity to develop targeted therapy, and has ulti- mately lead to the development of a new treatment paradigm. v vi Preface von Hippel–Lindau (VHL) Syndrome The von Hippel–Lindau (VHL) syndrome provided a unique opportunity to study the development of clear-cell tumors and delineate the genetic characteristics of this tumor. In sporadic renal cancer, both the maternal and paternal VHL alleles are inactivated by acquired mutations, whereas in the VHL syndrome the first mutation is inherited. Loss of VHL function may occur in ∼60–80% cases of sporadic clear- cell renal carcinomas (5). The VHL protein is the product of the VHL gene, functions as a tumor-suppressor gene, and is responsible for ubiquination of hypoxia-inducible factor-α (HIF-α) and its subsequent degradation by the proteosome (5). Under hypoxic conditions or in the presence of abnormal VHL function, HIF-α accumulates and activates the transcription of a variety of hypoxia-inducible genes. These include vascular endothelial growth factor (VEGF), platelet-derived growth factor-β (PDGF-β), transforming growth factor-α (TGF-α), and erythryopoietin (EPO). The VHL gene may control this process by suppressing angiogenesis, but loss of the VHL gene or its function allow increased secretion of factors such as VEGF and produces the vascular phenotype characteristic of clear-cell carcinoma. Blocking components of the VEGF pathway and/or the function of HIF-α is currently the major thera- peutic strategy for treatment or this malignancy, replacing immunotherapy with cytokines. Systemic Therapy: Metastatic Disease Immunotherapy consisting of interleukin-2 (IL-2) and/or interferon alpha (IFNα) had been the standard approaches for treatment of metastatic RCC, in addition to clinical trials investigating new agents. Responses were best with high-dose intra- venous IL-2 (21%) compared to low-dose intravenous IL-2 (11%) and subcutane- ous IL-2 (10%), although no survival advantage was observed (6). Similar response rates were reported comparing high-dose IL-2 (23.2%) versus subcutaneous IL-2 plus IFNα (9.9%) and again, no improvement in time to progression (TTP) or survival (7) were seen. IFNα has been established as the standard comparative treatment arm for Phase III clinical trials of new agents for the treatment of metastatic renal cancer. Several randomized trials have demonstrated improvement in medial survival for treated patients (8), and in a retrospective review a median OS of 13.1 months and a median TTP of 4.7 months for IFNα patients were reported (9). A major advance in the field during the past 10 years has been the recognition that a variety of clinical characteristics can be used to categorize patients into groups with differences in prognosis. For previously untreated patients a prognostic model was developed by investigators at Memorial Sloan Kettering Cancer Center (9) and then validated and expanded. Five clinical characteristics were identified (9) Preface vii and later validated at the Cleveland Clinic (10). These prognostic criteria have been utilized in Phase III clinical trials of the targeted agents, such as sorafenib, sunitinib, temsirolimus (CCI-779), and bevacizumab. The cloning of the VHL tumor-suppressor gene and the elucidation of its role in up-regulating growth factors associated with angiogenesis have provided insights into RCC biology, as well as defining a series of potential targets for novel thera- peutic approaches. The highly vascularized nature of this neoplasm has ultimately been utilized to control its growth and survival. VEGF and its receptors (VEGFR) are overexpressed in RCC compared to normal renal tissue, and VEGFR-2 is believed to be the major receptor mediating the angiogenic effects of VEGF (11). The binding of VEGF to the extracellular domain of the VEGFR induces tyrosine autophosphorylation and subsequent increases in tumor-associated angiogenesis, endothelial cell proliferation, migration, and enhanced survival. During the past 5 years a number of agents inhibiting the VEGF pathway have been investigated in advanced RCC patients, and a series of these have produced significant clinical benefit including increases in progression-free and OS. This group of novel agents has formed the central part of the new treatment para- digm for this tumor. The purpose of the current textbook is to provide an overview of these developments, as well as provide insights into the other targeted approaches that may ultimately play a role in the treatment of patients with this tumor. Chapters include a discussion of the biologic rationale for each target, as well as potential clinical approaches to provide inhibition of the pathway. The clinical data supporting the current approaches utilizing agents, such as sunitinib, sorafenib, temsirolimus, and bevacizumab, are outlined. In addition, novel targets including tumor necrosis factor, EGFR, Smac/DIABLO, and EpH2A are discussed in detail. The approval of three new agents for treatment of advanced RCC in 2007, and the likelihood that two additional drugs will receive regulatory approval in 2008–2009, make RCC a disease where not only significant clinical progress has occurred, but also an area that will be exploited to increase our understanding of how angiogenesis inhibitors function biologically and clinically. The treatment paradigm for patients with localized and advanced RCC has changed dramatically in the last 5–10 years. Surgical advances are now mirrored by the dramatic changes in therapy available for metastatic disease. The collection of chapters in this text provides an update for urologists, medical oncologists, and researchers interested in the biology and therapy of this tumor. References 1. American Cancer Society. Cancer Facts & Figures 2006. Atlanta, GA: Author; 2006. 2. Hock LM, Lynch J, Balaji KC. Increasing incidence of all stages of kidney cancer in the last 2 decades in the United States: an analysis of surveillance, epidemiology and end results program data. J Urol. 2002; 167: 57–60. 3. Russo P. Renal cell carcinoma: presentation, staging, and surgical treatment. Sem in Oncol. 2000; 27: 160–176. viii Preface 4. Kovacs G, Akhtar M, Beckwith BJ, et al. The Heidelberg classification of renal cell tumours. J Pathology. 1997; 183: 131–133. 5. Kim, W.Y., Kaelin, W.G. The role of VHL gene mutation in human cancer. J Clin Oncol. 2004; 22: 4991–5004. 6. Yang JC, Sherry RM, Steinberg SM, et al. Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer. J Clin Oncol. 2003; 21: 3127–3132. 7. McDermott DF, Regan MM, Clark JI, et al. Randomized phase III trial of high-dose inter- leukin-2 versus subcutaneous interleukin-2 and interferon in patients with metastatic renal cell carcinoma. J Clin Oncol. 2005; 23: 133–141. 8. Medical Research Council and Collaborators. Interferon alfa and survival in metastatic renal carcinoma: early results of a randomized controlled trial. Lancet. 1999; 353: 14–17. 9. Motzer RJ, Bacik J, Murphy BA, et al. Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol. 2002; 20: 289–296. 10. Mekhail TM, Abou-Jawde RM, BouMerhi G, et al. Validation and extension of the Memorial Sloan-Kettering prognostic factors model for survival in patients with previously untreated metastatic renal cell carcinoma. J Clin Oncol. 2005; 23: 832–841. 11. Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003; 9(6): 669–676. Contents Targeted Therapy for Metastatic Renal Cell Carcinoma: Overview ....... 1 Ronald M. Bukowski, Robert A. Figlin, and Robert J. Motzer Molecular Genetics in Inherited Renal Cell Carcinoma: Identification of Targets in the Hereditary Syndromes ............................. 13 Nadeem Dhanani, Cathy Vocke, Gennady Bratslavsky, and W. Marston Linehan Molecular Targets in Renal Tumors: Pathologic Assessment ................... 35 Ming Zhou Interferons and Interleukin-2: Molecular Basis of Activity and Therapeutic Results............................................................. 49 Thomas E. Hutson, Snehal Thakkar, Peter Cohen, and Ernest C. Borden The Molecular Biology of Kidney Cancer and Its Clinical Translation into Treatment Strategies ..................................... 79 William G. Kaelin Jr. and Daniel J. George VEGF: Biologic Aspects and Clinical Approaches ..................................... 99 W. Kimryn Rathmell and Brian I. Rini VEGF and PDGF Receptors: Biologic Relevance and Clinical Approaches to Inhibition ................................................................ 119 John S. Lam, Robert Figlin, and Arie Belldegrun Sunitinib and Axitinib in Renal Cell Carcinoma ....................................... 151 Robert J. Motzer Sorafenib in Renal Cell Carcinoma ............................................................. 167 Saby George and Ronald M. Bukowski ix x Contents Additional Tyrosine Kinase Inhibitors in Renal Cell Carcinoma ............. 189 Brian I. Rini Integrin a5b1 as a Novel Therapeutic Target in Renal Cancer ................ 195 Vanitha Ramakrishnan, Vinay Bhaskar, Melvin Fox, Keith Wilson, John C. Cheville, and Barbara A. Finck Carbonic Anhydrase IX: Biology and Clinical Approaches ...................... 211 Brian Shuch, Arie S. Belldegrun, and Robert A. Figlin Monoclonal Antibody G250 Recognizing Carbonic Anhydrase IX in Renal Cell Carcinoma: Biological and Clinical Studies ........................ 231 J. C. Oosterwijk-Wakka, Otto C. Boerman, Peter F. A. Mulders, and Egbert Oosterwijk Chemokines in Renal Cell Carcinoma: Implications for Tumor Angiogenesis and Metastasis ............................................................ 249 Karen L. Reckamp, Robert A. Figlin, and Robert M. Strieter PI3K/Akt/mTOR Pathway: A Growth and Proliferation Pathway .......... 267 Daniel Cho, James W. Mier, and Micheal B. Atkins EGFR and HER2: Relevance in Renal Cell Carcinoma ............................ 287 Eric Jonasch and Cheryl Lyn Walker Proteasome–NFkB Signaling Pathway: Relevance in RCC....................... 305 Jorge A. Garcia, Susan A.J. Vaziri, and Ram Ganapathi The Role of Hepatocyte Growth Factor Pathway Signaling in Renal Cell Carcinoma ............................................................................... 321 Benedetta Peruzzi, Jean-Baptiste Lattouf, and Donald P. Bottaro Smac/DIABLO: A Proapoptotic Molecular Target in Renal Cell Cancer ...................................................................................... 335 Yoichi Mizutani, Akihiro Kawauchi, Benjamin Bonavida, and Tsuneharu Miki EphA2: A Novel Target in Renal Cell Carcinoma...................................... 347 Mayumi Kawabe, Christopher J. Herrem, James H. Finke, and Walter J. Storkus Restoring Host Antitumoral Immunity: How Coregulatory Molecules Are Changing the Approach to the Management of Renal Cell Carcinoma ............................................................................... 367 Brant A. Inman, Xavier Frigola, Haidong Dong, James C. Yang, and Eugene D. Kwon Contents xi The Role of Gangliosides in Renal Cell Carcinoma ................................... 405 Philip E. Shaheen, Ronald M. Bukowski, and James H. Finke Tumour Necrosis Factor – Misnomer and Therapeutic Target ................ 425 Marina Parton, Tanya Das, Gaurisankar Sa, James Finke, Tim Eisen, and Charles Tannenbaum Molecular Markers for Predicting Prognosis of Renal Cell Carcinoma ............................................................................... 449 Mark Nogueira and Hyung L. Kim Adjuvant Therapy for Renal Cell Carcinoma: Targeted Approaches ..................................................................................... 473 A. Karim Kadar and Christopher G. Wood Index ................................................................................................................ 497