Table Of ContentR enal Cell Carcinoma
Robert A. Figlin ● W. Kimryn Rathmell
Brian I. Rini
Editors
Renal Cell Carcinoma
Translational Biology, Personalized
Medicine, and Novel Therapeutic Targets
Editors
Robert A. Figlin, M.D., F.A.C.P. W. Kimryn Rathmell, M.D., Ph.D.
Professor of Medicine and Biomedical Associate Professor of Medicine and Genetics
Sciences Lineberger Comprehensive Cancer Center
Director, Division of Hematology Oncology University of North Carolina
Department of Medicine Chapel Hill, NC, USA
Cedars-Sinai Medical Center
Associate Director for Academic Programs
Samuel Oschin Comprehensive Cancer
Institute
Professor Emeritus of Medicine
and Urology
David Geffen School of Medicine at UCLA
Los Angeles, CA, USA
Brian I. Rini, M.D., F.A.C.P.
Department of Solid Tumor Oncology
Cleveland Clinic Taussig Cancer Institute
Glickman Urological Institute
Cleveland, OH, USA
ISBN 978-1-4614-2399-7 e-ISBN 978-1-4614-2400-0
DOI 10.1007/978-1-4614-2400-0
Springer New York Dordrecht Heidelberg London
Library of Congress Control Number: 2012932089
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P reface
T remendous strides have been made in recent years in unraveling the aberrant biology
driving renal carcinomas. These discoveries have led to unparalleled shifts in the
treatment paradigm of this once devastating disease, historically known for its unre-
lenting progression of metastatic disease and high incidence of drug resistance and
fatality. Rapidly emerging new therapeutic strategies that have the ability to neutral-
ize this cancer have now engendered hope and optimism. In many instances, the
speed of advances in clinical management has outpaced the biology, and observa-
tions made in the clinic using new therapeutics have fueled scientifi c discovery. In
this way, renal cell carcinoma has truly served as a paradigm tumor type in the rapid
fl ux of discovery from bench to bedside and back to the bench.
T his textbook reviews and examines this enormously productive period with
chapters touching on every major topic area in the modern era of renal carcinoma
biology and treatment. Beginning with the discovery of the von Hippel Lindau
(V HL) gene in 1993, we now understand on a more fundamental level the associa-
tion of VHL mutation and the resultant HIF family stabilization as well as the inti-
mate relationship this axis plays in the development of clear cell renal cell carcinoma.
The unique and intricate genetics of this cancer are highly distinct from most other
tumors, and the advances made in this cancer beyond VHL biology have been intrin-
sically driven by discoveries from familial renal cell carcinomas linked with newer
large-scale genomic efforts in sporadic disease. The remarkable parallels of spo-
radic and familial diseases have enabled the elucidation of critical pathways in the
renal tumorigenic process. These genetic fi ndings fuel strategies to analyze and
defi ne sporadic tumors for greater accuracy in prognosis and prediction of response
to therapy, the latest of which will be detailed in this text. Completing the circle,
major new therapeutic strategies harness these biological discoveries, in particular
angiogenic, energy metabolism, chromatin remodeling, tumor microenvironment,
and classical signaling pathways. Many of these therapies have moved beyond
management of metastatic disease to arenas in combination with surgical approach
to advance the opportunities for durable remission or cure. This text will bring all of
these avenues of investigation together for readers interested in understanding the
v
vi Preface
dynamics of this fi eld in the last decade and anticipating a continued steep trajectory
in advancements toward the cure of this disease in its many manifestations.
T he fi eld does continue to evolve at an enormously rapid pace. In addition to
placing each of these major advances in historical context, the chapters in this text-
book take a critical look forward to consider the future advances in each topic. The
goal of this textbook is to educate the reader regarding the state of the art in renal
cancer biology and therapeutic strategies as well as to engage readers as participants
in an ongoing and exciting period of discovery and translation to advance the care
of patients with renal cell carcinoma.
Los Angeles, CA, USA Robert A. Figlin, M.D., F.A.C.P.
Chapel Hill, NC, USA W. Kimryn Rathmell, M.D., Ph.D.
Cleveland, OH, USA Brian I. Rini, M.D., F.A.C.P.
C ontents
Part I Biology of Renal Cell Carcinoma
1 The Genetic Basis of Kidney Cancer and Implications
for Targeted Therapies .......................................................................... 3
Laura S. Schmidt, Ramaprasad Srinivasan,
and W. Marston Linehan
2 Molecular Biology of Clear Cell Renal Carcinoma ............................ 27
William G. Kaelin Jr.
3 HIF Biology in RCC: Implications for Signaling,
Disease Progression, and Treatment..................................................... 49
W. Kimryn Rathmell
4 Tissue Biomarkers in Renal Cell Carcinoma:
Intermediate Endpoints in the Selection
of Targeted Agents for RCC .................................................................. 69
Brittany Bahamon and Sabina Signoretti
5 Molecular Characterization of Renal Cell Carcinoma ....................... 91
Bin Tean Teh, Leslie J. Farber, and Kyle Furge
Part II Current and Future Molecular Targets for RCC
6 Targeting the VEGF Pathway in Renal Cell Carcinoma.................... 115
Cristina Suarez and Brian I. Rini
7 Angiopoietins and Other Non-VEGF Antiangiogenic
Targets in Advanced Renal Cell Carcinoma........................................ 135
C. Lance Cowey and Thomas E. Hutson
8 Research Translation and Personalized Medicine .............................. 161
James Brugarolas
vii
viii Contents
9 Epigenetic Targeting and Histone Deacetylase
Inhibition in RCC .................................................................................. 193
Swathi Ramakrishnan and Roberto Pili
10 C-MET as a Novel Target for the Treatment
of Renal Cell Carcinoma ....................................................................... 213
Hema Vankayala, Patricia LoRusso, and Ulka Vaishampayan
11 Characterizing and Modulating the Tumor
Microenvironment in Renal Cell Carcinoma:
Potential Therapeutic Strategies........................................................... 239
Sumanta Kumar Pal, Karen Reckamp, Hua Yu,
and Robert A. Figlin
12 Carbonic Anhydrase IX: Its Role as a Biomarker,
Diagnostic, and Therapeutic Target
in Renal Cell Carcinoma ....................................................................... 253
E. Oosterwijk, A.B. Stillebroer, and P.F.A. Mulders
13 Presurgical Therapy for Renal Cell Carcinoma
and Implications for Window-of-Opportunity Trials ......................... 271
Hyung L. Kim, Edwin M. Posadas, and Robert A. Figlin
14 Mechanisms of Resistance to VEGF-Directed Therapy
and Implications for Future Trial Design ............................................ 283
James W. Mier
15 Vaccine-Based Immunotherapy and Targeting
the Tumor Microenvironment in Renal Cell Carcinoma ................... 305
Johannes Vieweg
Index ................................................................................................................ 323
C ontributors
B rittany B ahamon, B.S. D epartment of Pathology, Brigham and Women’s
Hospital, H arvard Medical School, B oston, M A, U SA
J ames B rugarolas, M .D., Ph.D. O ncology Division, Department of Internal
Medicine, University of Texas Southwestern Medical Center,
D allas, T X, U SA
Department of Developmental Biology,
University of Texas Southwestern Medical Center, Dallas, TX, US
C . L ance C owey, M .D. G enitourinary Oncology Program, B aylor-Sammons
Cancer Center, Texas Oncology, PA, D allas, T X, U SA
L eslie J . F arber, P h.D. N CCS-VARI Translational Research Laboratory,
N ational Cancer Centre and Duke-NUS Graduate Medical School, S ingapore
R obert A . F iglin, M .D., F.A.C.P. P rofessor of Medicine and Biomedical
Sciences, Director, Division of Hematology Oncology, Department of
Medicine, Cedars-Sinai Medical Center, Associate Director
for Academic Programs, Samuel Oschin Comprehensive
Cancer Institute, Professor Emeritus of Medicine and Urology,
D avid Geffen School of Medicine at UCLA,
L os Angeles, C A, U SA
K yle F urge, P h.D. V an Andel Research Institute, G rand Rapids, M I, U SA
T homas E . H utson, D .O., Pharm.D., F.A.C.P. G enitourinary Oncology
Program, B aylor-Sammons Cancer Center, Texas Oncology, PA, D allas, T X, U SA
W illiam G . K aelin J r., M .D. D epartment of Medical Oncology,
Dana-Farber Cancer Institute and Brigham and Women’s Hospital,
B oston, M A, U SA
Howard Hughes Medical Institute, Chevy Chase, MD, USA
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