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VOLUME SIXTY FIVE CURRENT CHALLENGES IN PERSONALIZED CANCER MEDICINE Edited by KEIRAN S. M. SMALLEY Department of Molecular Oncology, The Comprehensive Melanoma Research Center, Department of Cutaneous Oncology, The Moffitt Cancer Center Tampa, FL, USA Serial Editor S. J. ENNA Department of Molecular and Integrative Physiology, Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, USA Managing Editor LYNN LECOUNT University of Kansas Medical Center, School of Medicine, Kansas City, Kansas, USA ADVANCES IN PHARMACOLOGY Amsterdam • Boston • Heidelberg • London New York • Oxford • Paris • San Diego San Francisco • Sydney • Tokyo Academic Press is an imprint of Elsevier Academic Press is an imprint of Elsevier 225 Wyman Street, Waltham, MA 02451, USA 525 B Street, Suite 1900, San Diego, CA 92101-4495, USA Radarweg 29, PO Box 211, 1000 AE Amsterdam, The Netherlands The Boulevard, Langford Lane, Kidlington, Oxford, OX51GB, UK 32, Jamestown Road, London NW1 7BY, UK First edition 2012 Copyright Ó 2012 Elsevier Inc. All rights reserved No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means electronic, mechanical, photocopying, recording or otherwise without the prior written permission of the publisher Permissions may be sought directly from Elsevier's Science & Technology Rights Department in Oxford, UK: phone (+44) (0) 1865 843830; fax (+44) (0) 1865 853333; email: PREFACE rd th December 23 2011 marked the 40 year since President Richard Nixon signed the National Cancer Act declaring the “war on cancer”. Despite significant progress being made, cancer still remains the second leading cause of death in Western Societies, with 1 in 2 of all Americans expected to develop cancer at some point in their lifetimes. With growing rates of obesity, diabetes and poor nutrition afflicting society, the future incidence of cancer seems likely to increase and new strategies for the treatment and management of patients with advanced malignancies are urgently required. For many years the only therapies available for the treatment of advanced cancer have been cytotoxic drugs with modest selectivity for killing rapidly growing cancer cells over normal host cells. The general failure of these agents in most cancers, coupled with their narrow therapeutic windows and significant levels of toxicity, has led to the search for more selective anti- cancer drugs. The long held dream of cancer therapy, first espoused by Paul Ehrlich, has been the “magic bullet”; the ability to selectively kill malignant cells and to leave the healthy tissue unharmed (1). Thanks to the discoveries of the oncogene “revolution” and high throughput genomic sequencing we now understand a great deal about the underlying molecular basis of cancer and are coming closer to the reality that Ehrlich first postulated. It is now widely accepted that cancer is a disease of the genes and that tumors arise as a result of acquired genetic mutations. This realization has led to a shift from an “organ-centric” view of cancer to a more pathway-based, “oncogene- centric” view. Of therapeutic importance, it is now known that many types of cancer are uniquely dependent upon or “addicted” to signals from one oncogene for their survival and that dramatic anti-tumor responses can be achieved provided the correct oncogenic mutations are targeted (2). To date, small molecule inhibitors of Bcr-Abl, oncogenic BRAF, EGFR and Hedgehog signaling have been FDA-approved for chronic myeloid leukemia, BRAF mutant melanomas, sub-sets of non-small cell lung cancers (NSCLC) and locally advanced basal cell carcinoma, respectively (3-6). Although these new therapies have shown incredible promise in the clinic, responses have been have been mostly short-lived and resistance and disease relapse has been common (7). Strategies to further personalize cancer medicine, so that durable responses can be attained is likely to be a major xi j xii Preface research theme for both academic and industrial scientists for many years to come. For this volume of Advances in Pharmacology we have brought together some of the foremost basic science and clinical researchers to discuss some of the new frontiers in the development of targeted cancer therapy. The new age of personalized cancer therapy comes with a unique set of challenges for which the era of chemotherapy has provided little precedent. Data are already emerging showing that the inhibition of one signaling pathway or receptor tyrosine kinase (RTK), such the inhibition of BRAF in melanoma and EGFR in NSCLC, triggers compensatory signaling in parallel signaling pathways and RTKs, requiring rationally designed drug combinations. In other cases, the compensatory “escape” signaling may occur within the same pathway, as the result of altered feedback inhibition, so that one pathway will have to be targeted at multiple points (so-called vertical pathway inhibition). As we become better at targeting bulky disseminated disease, the chances of selecting for tumor cell clones that seed to therapeutically privileged sites such as the brain and the bone marrow are likely to increase, requiring novel strategies to co-target both the tumor and its sanctuary environment. Despite a drive towards more potent and specific therapies, a need still remains for more broadly targeted therapeutic agents, particularly for overcoming drug resistance. There is already good evidence from HER2 positive breast cancer and melanoma suggesting that resistance to EGFR and BRAF inhibitors could be overcome through combination with less specific agents, such as histone deacteylase inhibitors (HDAC) and heat shock protein (HSP)-90 inhibitors. At this stage, it is still not clear whether acquired drug resistance to targeted therapies arises following a process of adaptation and evolution or whether resistant clones (or even cancer stem cells) are already present prior to the initiation of therapy. The identification of the sub-population of cells within a tumor responsible for mediating resistance will prove critical in defining how therapeutic escape will be managed. Although still in its formative stages, the development of targeted cancer therapies has already shown incredible promise in a limited number of cancer types. As basic cancer research and drug development continues, we expect this number to grow and more patients to benefit from these exciting advances. Through better patient selection and novel strategies to manage resistance, a future can be envisaged in which cancer can be reduced to the level of a chronic, manageable disease. Funding:Work in the Smalley lab is supported by The National Cancer Institute (U54 CA143970-01 and R01 CA161107-01), The Harry Lloyd Preface xiii Trust and the State of Florida (09BN-14). The funders played no role in the preparation or contents of this manuscript. Keiran S.M. Smalley REFERENCES 1. Mukherjee, S. (2010). The emperor of all maladies: a biography of cancer. New York Scribner. 2. Sharma, S. V., Fischbach, M. A., Haber, D. A., & Settleman, J. (2006). Oncogenic shock": explaining oncogene addiction through differential signal attenuation. Clin Cancer Res, 12, 4392s–4395s 3. Yoshida, T., Zhang, G., & Haura, E. B. (2010). Targeting epidermal growth factor receptor: central signaling kinase in lung cancer. Biochem Pharmacol, 80, 613–623. 4. Druker, B. J., Talpaz, M., Resta, D. J., Peng, B., Buchdunger, E., Ford, J. M., et al. (2001). Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med, 344, 1031–1037. 5. Flaherty, K. T., Puzanov, I., Kim, K. B., Ribas, A., MacArthur, G. A., Sosman, J. A., et al. (2010). Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med, 363, 809–819. 6. Epstein, E. H. (2008). Basal cell carcinomas: attack of the hedgehog. Nat Rev Cancer, 8, 743–754. 7. Fedorenko, I. V., Paraiso, K. H., & Smalley, K. S. (2011). Acquired and intrinsic BRAF inhibitor resistance in BRAF V600E mutant melanoma. Biochem Pharmacol, 82, 201–209. CONTRIBUTORS Numbers in parenthesis indicate the pages on which authors’ contributions begin. Khaldoun Almhanna (437) Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA Andrew E. Aplin (315) Department of Cancer Biology and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA; Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA, USA Kate M. Bailey (63) Department of Imaging and Metabolism, H. Lee Moffitt Cancer Center, Tampa, FL, USA; Cancer Biology Ph.D. Program, University of South Florida, Tampa, FL, USA Kevin J. Basile (315) Department of Cancer Biology and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA Devraj Basu (235) Department of Otorhinolaryngology –– Head and Neck Surgery, University of Pennsylvania, Philadelphia, PA, USA; The Wistar Institute, Philadelphia, PA, USA; Philadelphia Veterans Administration Medical Center, Philadelphia, PA, USA Jose Conejo-Garcia (45) Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA, USA Carlotta Costa (519) Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02129, USA Michael A. Davies (109) Department of Melanoma Medical Oncology, Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA Ken Dutton-Regester (399) Queensland Institute of Medical Research, Oncogenomics Laboratory, Brisbane QLD 4006, Australia; Faculty of Science and Technology, Queensland University of Technology, Brisbane QLD 4000, Australia Hiromichi Ebi (519) Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02129, USA xvj xvi Contributors Michael F. Emmons (143) Molecular Oncology Program, H Lee Moffitt Cancer Center, Tampa, FL, USA; Cancer Biology Program, University of South Florida, Tampa, FL, USA Jeffrey A. Engelman (519) Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02129, USA Anthony C. Faber (519) Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02129, USA Nicole Facompre (235) Department of Otorhinolaryngology –– Head and Neck Surgery, University of Pennsylvania, Philadelphia, PA, USA; The Wistar Institute, Philadelphia, PA, USA Omar E. Franco (267) Department of Urologic Surgery, Vanderbilt University, Nashville, TN, USA Stuart Gallagher (27) Kolling Institute, Royal North Shore Hospital, University of Sydney, Sydney, Australia Anthony W. Gebhard (143) Molecular Oncology Program, H Lee Moffitt Cancer Center, Tampa, FL, USA; Molecular Pharmacology and Physiology Program, University of South Florida, Tampa, FL, USA Robert J. Gillies (63) Department of Imaging and Metabolism, H. Lee Moffitt Cancer Center, Tampa, FL, USA; Department of Radiology, H. Lee Moffitt Cancer Center, Tampa, FL, USA Arig Ibrahim Hashim (63) Department of Imaging and Metabolism, H. Lee Moffitt Cancer Center, Tampa, FL, USA Simon W. Hayward (267) Department of Urologic Surgery, Vanderbilt University, Nashville, TN, USA Nicholas K. Hayward (399) Queensland Institute of Medical Research, Oncogenomics Laboratory, Brisbane QLD 4006, Australia Lori A. Hazlehurst (143) Molecular Oncology Program, H Lee Moffitt Cancer Center, Tampa, FL, USA; Molecular Pharmacology and Physiology Program, University of South Florida, Tampa, FL, USA; Cancer Biology Program, University of South Florida, Tampa, FL, USA Meenhard Herlyn (235, 335) Molecular and Cellular Oncogenesis Program, Melanoma Research Center, The Wistar Institute, Philadelphia, USA Peter Hersey (27) Oncology and Immunology Unit, University of Newcastle, Newcastle, Australia; Kolling Institute, Royal North Shore Hospital, University of Sydney, Sydney, Australia Contributors xvii Qinghua Huang (191) Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL 33136, USA Komal Jhaveri (471) Breast Cancer Medicine Service, Department of Medicine, Memorial Sloan-Kettering, Cancer Center, NY, USA Lei Jin (27) Kolling Institute, Royal North Shore Hospital, University of Sydney, Sydney, Australia Harriet M. Kluger (1) Section of Medical Oncology, Yale Cancer Center, Yale University School of Medicine, New Haven, CT, USA Fritz Lai (27) Oncology and Immunology Unit, University of Newcastle, Newcastle, Australia Zhao-Jun Liu (191) Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA SubbaRao V. Madhunapantula (361) Jagadguru Sri Shivarathreeshwara Medical College, Jagadguru Sri Shivarathreeshwara University, Mysore, Karnataka, India Branka Mijatov (27) Kolling Institute, Royal North Shore Hospital, University of Sydney, Sydney, Australia Shanu Modi (471) Breast Cancer Medicine Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, NY, USA; Weill Cornell Medical College, NY, USA Rajesh R. Nair (143) Molecular Oncology Program, H Lee Moffitt Cancer Center, Tampa, FL, USA Hiroshi Nakagawa (235) Department of Medicine, Division of Gastroenterology, University of Pennsylvania, Philadelphia, PA, USA Gavin P. Robertson (361) Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, PA, USA; Department of Pathology, The Pennsylvania State University College of Medicine, Hershey, PA, USA; Department of Dermatology, The Pennsylvania State University College of Medicine, Hershey, PA, USA; Department of Surgery, The Pennsylvania State University College of Medicine, Hershey, PA, USA; Penn State Melanoma Center, The Pennsylvania State University College of Medicine, Hershey, PA, USA; Penn State Melanoma Therapeutics Program, The Pennsylvania State University College of Medicine, Hershey, PA, USA; The Foreman Foundation for Melanoma Research, The Pennsylvania State University College of Medicine, Hershey, PA, USA xviii Contributors David Shahbazian (1) Section of Medical Oncology, Yale Cancer Center, Yale University School of Medicine, New Haven, CT, USA Hongwei Shao (191) Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL 33136, USA Rajasekharan Somasundaram (335) Molecular and Cellular Oncogenesis Program, Melanoma Research Center, The Wistar Institute, Philadelphia, USA Joshua Sznol (1) Section of Medical Oncology, Yale Cancer Center, Yale University School of Medicine, New Haven, CT, USA Julia Tchou (45) Division of Endocrine and Oncologic Surgery, Department of Surgery, and the Rena Rowan Breast Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA Jessie Villanueva (335) Molecular and Cellular Oncogenesis Program, Melanoma Research Center, The Wistar Institute, Philadelphia, USA Jonathan W. Wojtkowiak (63) Department of Imaging and Metabolism, H. Lee Moffitt Cancer Center, Tampa, FL, USA Xu Dong Zhang (27) Oncology and Immunology Unit, University of Newcastle, Newcastle, Australia CHAPTER ONE Vertical Pathway Targeting in Cancer Therapy David Shahbazian, Joshua Sznol, Harriet M. Kluger Section of Medical Oncology, Yale Cancer Center, Yale University School of Medicine, New Haven, CT, USA Abstract Malignant cells arise from particular mutations in genes controlling cell proliferation, invasion, and survival. Older antineoplastic drugs were designed to target vital cellular processes, such as DNA maintenance and repair and cell division. As a result, these drugs can affect all proliferating cells and are associated with unavoidable toxicities. Recent discoveries in cancer research have identified “driver” mutations in some types of cancer, and efforts have been undertaken to develop drugs targeting these onco- genes. In most cases, due to escape mechanisms and adaptive responses, single oncogene targeting is insufficient to induce prolonged responses in solid tumors. Drug combinations are therefore used to enhance the growth inhibitory and cytotoxic effects of the targeted therapies. Depending on the position of additional targets within the signaling network, drug combinations may target either different signaling pathways (parallel targeting) or the same pathway at several fragile nodes (vertical targeting). In this review, we discuss strategies of multitarget inhibition with a focus on vertical signaling pathway targeting. 1. INTRODUCTION Cancer is the second most frequent cause of mortality worldwide and the leading cause of death in developed countries ( Jemal et al., 2011). While early stage solid tumors are curable by surgical resection and/or adjuvant therapy, disseminated cancers typically have a poor prognosis and require alternative therapeutic approaches, including the targeting of cellular mechanisms supporting uncontrolled cellular proliferation and metastasis. There are over 100 types of cancer which affect virtually every organ or tissue in the human body. Until recently, most chemotherapies used in clinical practice targeted vital cellular processes such as DNA replication/ repair (e.g., nucleotide analogs and intercalating agents) and cell division (including drugs inhibiting polymerization of cytoskeletal proteins) in a nonspecific fashion. This indiscriminate approach is toxic to any Advances in Pharmacology, Volume 65 Ó 2012 Elsevier Inc. ISSN 1054-3589, All rights reserved. 1j http://dx.doi.org/10.1016/B978-0-12-397927-8.00001-4