Medicine Giaccone Soria TARGETED THERAPIES IN ONCOLOGY SECOND EDITION S E C O N D E D I T I O N Since the last edition of this book, major advances have been made in our understanding of key pathways that control tumor progression. This has led T A R G E T E D to the development of new anticancer agents that have the ability to block T the activity of proteins involved in neoplastic cell development and prolifera- A tion. Targeted Therapies in Oncology, Second Edition provides a concise R timely panorama of existing targeted therapies and progress into future G anticancer treatments. T H E R A P I E S E These therapies notably include: T in • Targeted agents of immune checkpoints E • Signal-transduction inhibitors D • Antiangiogenic agents O N C O L O G Y • Vascular-disrupting agents T • Apoptosis modulators H • Stem cell inhibitors E • Tumor profiling for drug development R The book emphasizes the biology behind this new class of drugs as well as A the clinical achievements obtained. The contributors to this volume stand at P the cutting edge of cancer research and treatment around the world. I E S About the Editors: Giuseppe Giaccone is a professor and associate director of the Lombardi I N Cancer Center at Georgetown University in Washington, D.C. Professor Giaccone has written more than 500 peer-reviewed scientific papers and O several books and book chapters and is a board member of several international scientific journals. His fields of research include lung cancer N and the development of novel anticancer agents. He has organized a C number of international conferences, including the Topoisomerase Sympo- O sia and the Targeted Anticancer Therapy conferences. L Jean-Charles Soria is a professor of medicine at South-Paris University, O France, and adjunct professor at the University of Texas: MD Anderson G Cancer Center. He is the chairman of the Early Drug Development Depart- Y ment at Gustave-Roussy, Villejuif, France. Professor Soria has authored over 300 peer-reviewed scientific papers. His main research interests include early clinical development across solid tumors, pharmacodynamic biomarkers, lung cancer, and personalized medicine. He is also involved in translational research related to precision medicine, DNA repair, and tumor progression, notably in lung cancer models. E d i t e d b y S E C O N D Giuseppe Giaccone H100477 E D I T I O N Jean-Charles Soria T A R G E T E D T H E R A P I E S in O N C O L O G Y T A R G E T E D T H E R A P I E S in O N C O L O G Y E d i t e d b y Giuseppe Giaccone Jean-Charles Soria Boca Raton London New York CRC Press is an imprint of the Taylor & Francis Group, an informa business CRC Press Taylor & Francis Group 6000 Broken Sound Parkway NW, Suite 300 Boca Raton, FL 33487-2742 © 2014 by Taylor & Francis Group, LLC CRC Press is an imprint of Taylor & Francis Group, an Informa business No claim to original U.S. Government works Version Date: 20130918 International Standard Book Number-13: 978-1-84214-546-3 (eBook - PDF) This book contains information obtained from authentic and highly regarded sources. While all reasonable efforts have been made to publish reliable data and information, neither the author[s] nor the publisher can accept any legal responsibil- ity or liability for any errors or omissions that may be made. 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Visit the Taylor & Francis Web site at http://www.taylorandfrancis.com and the CRC Press Web site at http://www.crcpress.com Contents Preface.......................................................................................................................ix Acknowledgments .....................................................................................................xi Editors ....................................................................................................................xiii Contributors .............................................................................................................xv Chapter 1 Role of Next-Generation Sequencing Technologies .............................1 Siddhartha Devarakonda, Daniel Morgensztern, and Ramaswamy Govindan Chapter 2 Signal Transduction Inhibitors of the HER Family ...........................17 Christina Brzezniak, Corey Carter, Anish Thomas, and Giuseppe Giaccone Chapter 3 HER2 Inhibition and Clinical Achievements ....................................51 Berta Sousa, Joana Ribeiro, and Fatima Cardoso Chapter 4 Inhibiting the Phosphoinositide 3-Kinase/AKT/Mammalian Target of Rapamycin Pathway ............................................................81 Simona Wagner and Janet E. Dancey Chapter 5 BRAF and MEK Inhibitors ..............................................................115 Lidia Robert and Antoni Ribas Chapter 6 KIT and KIT Inhibitors ....................................................................127 Jean-Yves Blay, Armelle Dufresne, Olfa Derbel, and Isabelle Ray-Coquard Chapter 7 Targeting the Fibroblast Growth Factor Receptor Pathway in Human Cancer ..................................................................................157 Maria Vittoria Dieci and Fabrice Andre Chapter 8 Anaplastic Lymphoma Kinase .........................................................173 Aparna Rao and Benjamin Solomon v © 2010 Taylor & Francis Group, LLC vi Contents Chapter 9 MET Inhibitors .................................................................................191 Apoorva Chawla, Ravi Salgia, and Victoria M. Villaflor Chapter 10 Targeting Stem Cells ........................................................................217 Marcello Maugeri-Saccà and Ruggero De Maria Chapter 11 The Cancer Super-Chaperone Hsp90: Its Posttranslational Regulation and Drug Targeting ........................................................235 Annerleim Walton-Diaz, Sahar Khan, Jane B. Trepel, Mehdi Mollapour, and Len Neckers Chapter 12 Targeting Apoptosis Pathways .........................................................253 Pamela M. Holland, David Reese, and Jeffrey Wiezorek Chapter 13 Targeting Angiogenesis ....................................................................283 Sophie Postel-Vinay and Jean-Pierre Armand Chapter 14 Antivascular Agents .........................................................................315 Gianluca Del Conte and Cristiana Sessa Chapter 15 Immunotherapy: CTLA4, PD-1, PD-L1, IL-18, and IL-21 ..............325 Patrick M. Forde and Julie R. Brahmer Chapter 16 Vaccine Therapy and Integration with Other Modalities .................341 Benedetto Farsaci, Peter S. Kim, James W. Hodge, Claudia Palena, James L. Gulley, and Jeffrey Schlom Chapter 17 Histone Deacetylase Inhibitors as Targeted Therapies ....................367 Alexandra Zimmer, Arup R. Chakraborty, Robert W. Robey, and Susan E. Bates Chapter 18 Compounds Targeting Androgen Pathways .....................................401 Aurelius Omlin, Carmel Pezaro, and Johann de Bono Chapter 19 Targeting DNA Repair: PARP and Chk1 Inhibitors ........................423 Peter Stephens and Ruth Plummer © 2010 Taylor & Francis Group, LLC Contents vii Chapter 20 Inhibitors Targeting Mitosis .............................................................445 Dan L. Sackett, Edina Komlodi-Pasztor, and Tito Fojo © 2010 Taylor & Francis Group, LLC Preface Rapid advances in tumor biology have led to the identification of the molecular circuitry that governs cancer cell proliferation. Better understanding of the key pathways that control tumor progression has enabled the pharmaceutical industry and academia to develop new anticancer agents targeting specific molecular events involved in the oncogenic process. The term “targeted therapies” refers to treatment strategies directed against molecular targets considered to be involved in the process of neoplastic transforma- tion. This is not a brand new concept in oncology, since hormonal manipulations have long been applied for the treatment of advanced and early-stage breast, prostate, and thyroid cancers. In the past 30 years, characteristic alterations of neoplastic cells have been described, such as specific translocations, activating mutations, or gene amplifica- tions, which have brought significant changes to the nosological classification of cancers. The molecular classification of some cancers has contributed to the develop- ment of a new class of drugs that aims at blocking, with various degrees of specific- ity, the activity of proteins involved in neoplastic cell development and progression. This book provides a concise and up-to-date panorama of existing targeted therapies and those being developed into valuable anticancer treatments, with an emphasis on the “clinical achievements” obtained with the aforementioned anticancer agents. The biology behind each target has also been discussed. The chapters included reflect a variety of targeted therapies aiming at blocking a wide array of “hallmarks of cancer.” These therapies notably include signal-transduction inhibitors, antiangiogenic and vascular-disrupting agents, apoptosis modulators, and targeted agents of immune checkpoints; however, only the targeted agents that have already entered the clinical arena have been included. The introduction of these agents has already had a large impact across different tumor types and in early- as well as advanced-stage cancer. Giuseppe Giaccone Jean-Charles Soria ix © 2010 Taylor & Francis Group, LLC