Molecular Basis for Therapy of AIDS-Defining Cancers Dirk P. Dittmer · Susan E. Krown Editors Molecular Basis for Therapy of AIDS-Defining Cancers 123 Editors Dirk P. Dittmer Susan E. Krown Associate Professor Member Department of Microbiology Melanoma and Sarcoma Service and Immunology Division of Solid Tumor Oncology Department of Medicine Lineberger Comprehensive Memorial Sloan-Kettering Cancer Center Cancer Center Center for AIDS Research 1275 York Avenue 715 Mary Ellen Jones, CB 7290 New York, NY 10065 University of North Carolina Professor of Medicine at Chapel Hill Weill Cornell Medical College Chapel Hill, NC 27599-7290 New York, NY [email protected] [email protected] ISBN 978-1-4419-1512-2 e-ISBN 978-1-4419-1513-9 DOI 10.1007/978-1-4419-1513-9 Springer New York Dordrecht Heidelberg London Library of Congress Control Number: 2010926491 © Springer Science+Business Media, LLC 2010 All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (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 identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights. While the advice and information in this book are believed to be true and accurate at the date of going to press, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein. Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com) We dedicate this book to the memory of our friend and colleague William J. Harrington Jr. Foreword More than 25 years into the AIDS pandemic, cancers that develop in individuals infected with human immunodeficiency virus (HIV) continue to challenge epidemi- ologists, virologists, molecular biologists, immunologists, and clinicians treating affected patients in both developed and resource-limited environments. The recog- nition that Kaposi’s sarcoma (KS) and later, aggressive, B-cell, non-Hodgkin’s lymphomas (NHLs) were developing at alarmingly high rates in young adults with an acquired form of immune deficiency predated the discovery of HIV by several years and a diagnosis of either of these tumors became part of the early case def- initions of AIDS. These malignancies, both of which are associated with human herpesviruses, and invasive cervical cancer, which is linked to infection with cer- tain human papillomaviruses (HPVs), remain the only cancers considered as “AIDS defining” according to the CDC definition. The relatively recent widespread availability in developed countries of drug regimens that can effectively suppress HIV infection and maintain or restore cell-mediated immune function has modified the occurrence of at least some HIV- associated cancers. In particular, the incidence of KS has decreased markedly, NHL less so, but neither has been eliminated even among individuals receiving appar- ently effective antiretroviral therapy. At the same time, as HIV-infected individuals live longer – often with incompletely reconstituted immune function – the popu- lation at risk for both AIDS-associated cancers and other cancers not specifically associated with HIV infection (but often affecting older individuals or associated with other, known risk factors) has increased. These so-called non-AIDS-defining cancers (NADCs) include those associated with viruses (e.g., anal cancer, penile cancer, Hodgkin’s disease, hepatocellular cancer, Merkel cell cancers) and those associated with environmental factors (e.g., lung cancer, head and neck cancers). In resource-limited settings where antiretroviral therapy has reached only a small fraction of the HIV-infected population, and where infection with the KS her- pesvirus (KSHV/HHV-8) and oncogenic HPV types is far more common than in the developed world, KS and invasive cervical cancer continue to be leading causes of morbidity and mortality among HIV-infected individuals. Thus, there is a need to understand the mechanisms involved in the development of these varied tumor types so that we can improve the options available for their prevention and treatment. vii viii Foreword In this volume, we have assembled expert reviews on the epidemiology of can- cer in HIV-infected individuals, the particular challenges of HIV-associated cancer management in resource-limited settings and opportunities for collaborations that can advance both science and clinical care in those settings, and a series of articles that consider the biology of cancers in HIV and suggest ways in which improved insights into tumor pathogenesis may lead to innovative therapeutic strategies. Although these latter articles by no means exhaustively cover the entire spectrum of tumor types or potential mechanism-driven approaches to therapy of HIV-associated malignancies, they give a sampling of the rich possibilities that currently exist for novel therapeutic approaches and should inspire further investigations in this important and challenging area. New York, NY Susan E. Krown Chapel Hill, NC Dirk P. Dittmer Contents The Epidemiology of Cancer in People with HIV ............. 1 Andrew E. Grulich, Diego Serraino, and Denise Whitby Epidemiology and Clinical Characteristics of Non-AIDS-Defining Malignancies .................... 17 Elizabeth Y. Chiao HIV-Related Cancer Management in Resource-Limited Settings: A Case Study of Malawi ..................... 41 Mina C. Hosseinipour Immunology of HIV-Associated Kaposi Sarcoma ............. 59 Ashok Cattamanchi and Corey Casper Targeting Signal Transduction Pathways for the Treatment of Kaposi Sarcoma .............................. 79 Janet L. Douglas, Henry B. Koon, and Ashlee V. Moses Role of NF-κB Inhibitors in HIV-Related Malignancies ......... 95 Erin Gourley Reid and Dirk P. Dittmer The Molecular Basis of Lytic Induction Therapy in Relation to Gamma herpesvirus (KSHV, EBV)-Associated, AIDS-Related Tumors .................................... 111 Shannon C. Kenney and Joyce D. Fingeroth Viral Interleukin-6: Molecular Biology and Pathogenesis ........ 137 John Nicholas Targeting the PI3K/Akt/mTOR Pathway in AIDS-Associated Malignancies ................................. 153 Blossom Damania Restoration of p53 Function by MDM2 Inhibition: Potential Strategy to Treat KSHV-Associated Malignancies ............ 167 Grzegorz Sarek and Päivi M. Ojala ix x Contents Interferon in Kaposi’s Sarcoma Biology and Therapy .......... 181 Susan E. Krown Metronomic Therapy for HIV-Associated Malignancies ......... 199 Rosemary Rochford and Scot C. Remick Targeting EGFR in HPV-Associated Cancer ............... 211 Joseph A. Sparano, Missak Haigentz, and Mark H. Einstein Cidofovir Against Human Papillomavirus-Associated Diseases ..... 235 Elizabeth A. Stier Subject Index ................................. 247 Contributors Corey Casper, M.D., MPH Department of Epidemiology, University of Washington, Seattle, WA, USA; Vaccine and Infectious Disease Institute, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA, [email protected] Ashok Cattamanchi, M.D. Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA, [email protected] Elizabeth Yu Chiao, M.D. Department of Medicine, Sections of Infectious Diseases and Health Services Research, Baylor College of Medicine, Houston, TX 77030, USA; Houston VA Medical Center (152), Houston, TX 77030, USA; Houston Center for Quality of Care and Utilization Studies, Houston, TX 77030, USA, [email protected] Blossom Damania, Ph.D. Department of Microbiology and Immunology, School of Medicine, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA, [email protected] Dirk P. Dittmer, Ph.D. Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Center, Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7290, USA, [email protected] Janet L. Douglas, Ph.D. Vaccine & Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR 97006, USA, [email protected] Mark H. Einstein, M.D., M.S. Clinical Research, Division of Gynecologic Oncology, Albert Einstein College of Medicine, Montefiore Cancer Center-Weiler Division, Bronx, NY 10461, USA, meinstei@montefiore.org Joyce D. Fingeroth, M.D. Division of Infectious Diseases, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA, jfi[email protected] Erin Gourley Reid, M.D. Department of Medicine (Hematology), Moores UCSD Cancer Center, La Jolla, CA 92093-0987, USA, [email protected] xi xii Contributors Andrew E. Grulich, M.B.B.S., Ph.D. National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, 2010 Sydney, Australia, [email protected] Missak Haigentz, Jr., M.D. Albert Einstein College of Medicine, Montefiore Cancer Center-Weiler Division, Bronx, NY 10461, USA, mhaigent@montefiore.org Mina C. Hosseinipour, M.D., M.P.H. Division of Infectious Diseases, University