checkpoint controls and targets in cancer therapy978-1-60761-178-3/1.pdf · checkpoint controls and...

BookID 157084_ChapID FM1_Proof# 1 - 14/08/2009

Checkpoint Controls and Targets in Cancer Therapy

BookID 157084_ChapID FM1_Proof# 1 - 14/08/2009 BookID 157084_ChapID FM1_Proof# 1 - 14/08/2009

Cancer Drug Discovery and Development Series

Beverly A. Teicher, PhD, Series Editor

For other titles published in the series, go towww.springer.com/humanaselect the subdisciplinesearch for your title


Checkpoint Controls and Targets in Cancer Therapy

Edited by

Zahid H. Siddik

University of Texas, M.D. Anderson Cancer Center, Houston, Texas, USA


EditorZahid H. SiddikDepartment of Experimental TherapeuticsThe University of Texas M.D. Anderson Cancer Center1515 Holcombe BoulevardHouston, TX [email protected]

Series EditorBeverly A. Teicher, PhDDepartment of Oncology ResearchGenzyme CorporationFramingham, MA, USA

ISBN 978-1-60761-177-6 e-ISBN 978-1-60761-178-3DOI 10.1007/978-1-60761-178-3Springer Dordrecht Heidelberg London New York

Library of Congress Control Number: 2009933775

© Humana Press, a part of Springer Science+Business Media, LLC 2010All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Humana Press, 999 Riverview Drive, Suite 208, Totowa, NJ 07512 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)


For Jaan, Bubbloo, Bubbly and Pupsee,The Essentials of Life

vii


Much work over the last two decades has firmly established that loss of cell cycle checkpoint regu-lation, and resultant unabated cellular proliferation, is an inherent characteristic of cancer. This loss can occur through aberration in any one single compo-nent of the many signal transduction pathways that orchestrate checkpoint regulation, and results in either a failure to activate the checkpoint or a fail-ure to respond to the activated checkpoint. In nor-mal cells, checkpoint pathways are activated when genetic or cellular homeostasis is compromised, and signals are then transduced to re-establish basal conditions, and, failing this, to activate the apoptotic machinery to induce a cellular suicidal response. This implies that both survival and cell death pathways are induced following checkpoint activation, and that the final decision by the cell to live or die is dependent on the net result from integrating two opposing sets of signals.

It is intriguing that checkpoint pathways are also critical in cancer therapy to provide an apoptotic stimulus in tumor cells when cellular damage induced by the therapeutic agent is detected by the sensor system. Therefore, it is not surprising that failure in pro-apoptotic signals following DNA dam-age induces therapeutic resistance. Understanding the intricacies of checkpoint response is, therefore, central not only for identifying key checkpoint targets in tumor cells, but also for the design of therapeutic regimen that will enhance antitumor effects. Although early versions of this design entail empirical combinations of cytotoxic agents with cell cycle or checkpoint inhibitors, a greater understanding of the concepts could make such combinations more rational and, thereby, clinically

more effective. Toward that goal, the contributions in this book will consolidate the current state of knowledge on checkpoint responses and provide the status of targets under investigation for poten-tial therapeutic exploitation.

The immediate attraction of the book to the scientific community is that it represents a timely opportunity to build upon existing views of checkpoints and expand our understanding of the inner workings of the critical checkpoint machinery. The accumulating knowledge over the past several decades has provided ample appre-ciation that response to checkpoint activation is manifested through coordinated inhibition of cyclin-dependent kinase (CDK) complexes in G1, S, and/or the G2 phase in order to arrest the cell cycle. Kinase inhibition can occur through several mechanisms, including inhibitory phosphoryla-tion of CDK, destruction of the cognate cyclins, and recruitment of CDK inhibitors from the INK and WAF1/CIP1 families. However, the wealth of information from recent discoveries needs to be examined critically to expand our horizons. At the same time, there is acute awareness that checkpoint response varies depending on the cytotoxic agent, and this serves as a reminder of the magnitude of complexity that is inherent in checkpoint regulation. This volume is intended to bring the cancer research community closer toward a better understanding of this regulation, and how checkpoint abnormalities can promote cancer progression and impact negatively on chemotherapeutic outcome.

This book brings together renowned experts, who are defining the field of checkpoints, and as

Preface

viii


Preface

such it represents a unique collection of insight-ful contributions that will serve as an important resource for both the research community and the medical oncologists. Since checkpoint regulation

is inextricably linked to cancer development and cancer therapy, the contents of this book will be of significant interest and appeal to both basic and translational investigators alike.

Zahid H. Siddik, Ph.D.

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Preface .................................................................................................................................................. vii

Part I Circuitry of Checkpoint Response

1. Evasion of G1 Checkpoints in Cancer .......................................................................................... 3Krijn K. Dijkstra, Cristophe Blanchetot, and Johannes Boonstra

2. Distinct Pathways Involved in S-Phase Checkpoint Control ........................................................ 27Paula J. Hurley and Fred Bunz

3. Mechanisms of G2 Phase Arrest in DNA Damage-Induced Checkpoint Response ..................... 37Jian Kuang and Ruoning Wang

4. Centrosomes in Checkpoint Responses ........................................................................................ 53Alwin Krämer

5. Interplay of 14-3-3 Family of Proteins with DNA Damage-Regulated Molecules in Checkpoint Control ................................................................................................................... 69Mong-Hong Lee, Sai-Ching Jim Yeung, and Heng-Yin Yang

Part II Checkpoint Response and the Aetiology of Cancer

6. Chromatin Modifications and Orchestration of Checkpoint Response in Cancer ........................ 83Makoto Nakanishi

7. DNA Damage Response and the Balance Between Cell Survival and Cell Death ....................... 95Bernd Kaina, Wynand P. Roos, and Markus Christmann

8. Dysfunction of the RB Retinoblastoma Gene in Cancer .............................................................. 109Francesca Pentimalli, Letizia Cito, and Antonio Giordano

9. G1 Phase Cyclins in Cancer Development and Progression ......................................................... 123John Patrick Alao

Contents

x


Contents

10. The BRCA1/2 Pathway Prevents Some Leukemias and Lymphomas in Addition to Breast/Ovarian Cancers: Malignancies that Overcome Checkpoint Controls ........................ 155Bernard Friedenson

Part III Targeting Checkpoint Response in Cancer Therapy

11. Regulation of p53 Activity and Associated Checkpoint Controls .............................................. 171Sean M. Post, Alfonso Quintás-Cardama, and Guillermina Lozano

12. The Importance of p53 Signaling in the Response of Cells to Checkpoint Inhibitors ............... 189Alan Eastman

13. Targeting p21-Dependent Pathways for Cell Death in Cancer Therapy ..................................... 199Zahid H. Siddik

14. p27Kip1 as a Biomarker and Target for Treatment of Cancer .................................................... 215Xiao-Feng Le and Robert C. Bast Jr.

15. Targeting Cyclin-Dependent Kinases with Small Molecule Inhibitors ...................................... 235Paolo Pevarello, James R. Bischoff, and Ciro Mercurio

16. Chk1 and Chk2 as Checkpoint Targets ....................................................................................... 245Haiying Zhang, Zhan Xiao, and Tom Sowin

17. Targeting Cdc25 Phosphatases in Cancer Therapy ..................................................................... 261Johannes Rudolph

Index .................................................................................................................................................... 271

Contributors

John Patrick Alao, Ph.D.Department of Cell and Molecular Biology, Lundberg Laboratory, University of Gothenburg, S-405 30 Göteborg, Sweden, [email protected]

Robert C. Bast, Jr., M.D. Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA, [email protected]

James R. Bischoff, Ph.D. Experimental Therapeutics Programme, Centro Nacional de Investigaciones Oncologicas (CNIO), 28029 Madrid, Spain

Cristophe Blanchetot, Ph.D. Cellular Architecture and Dynamics, Institute of Biomembranes, 3584 CH Utrecht, The Netherlands

Johannes Boonstra, Ph.D.University College Utrecht, 3508 BE Utrecht, The Netherlands Cellular Architecture and Dynamics, Institute of Biomembranes, 3584 CH Utrecht, The Netherlands, [email protected]

Fred Bunz, M.D., Ph.D. Department of Radiation Oncology and Molecular Radiation Sciences and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA, [email protected]

Markus Christmann, Ph.D. Department of Toxicology, University of Mainz, D-55131 Mainz, Germany

Letizia Cito, Ph.D. CROM – Center of Oncology Research Mercogliano, Avellino, Italy

Krijn K. Dijkstra, B.Sc. University College Utrecht, 3508 BE Utrecht, The Netherlands


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xii

Alan Eastman, Ph.D.Department of Pharmacology and Norris Cotton Cancer Center, Dartmouth Medical School, Lebanon, NH 03756, USA, [email protected]

Bernard Friedenson, Ph.D.Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois Chicago, Chicago, IL 60607, USA, [email protected]

Antonio Giordano, M.D., Ph.D.CROM – Center of Oncology Research Mercogliano, Avellino, Italy Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA, [email protected] of Human Pathology and Oncology, University of Siena, Siena, Italy

Paula J. Hurley, Ph.D.Department of Radiation Oncology and Molecular Radiation Sciences and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA

Bernd Kaina, Ph.D.Department of Toxicology, University of Mainz, D-55131 Mainz, Germany [email protected]

Alwin Krämer, M.D.Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center and Department of Internal Medicine V, University of Heidelberg, 69120 Heidelberg, Germany, a.kraemer@dkfz-heidelberg

Jian Kuang, Ph.D.Department of Experimental Therapeutics, Division of Cancer Medicine, M. D. Anderson Cancer Center, Houston, TX 77030, USA, [email protected]

Xiao-Feng Le, M.D., Ph.D. Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA

Mong-Hong Lee, Ph.D.Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA, [email protected] The Program in Genes & Development, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA

Guillermina Lozano, Ph.D. Department of Genetics, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA, [email protected]

Ciro Mercurio, Ph.D. DAC Srl c/o Campus IFOM-IEO, Via Adamello 16, 20139 Milano, Italy


Contributors

xiii

Makoto Nakanishi, M.D., Ph.D.Department of Cell Biology, Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan, [email protected]

Francesca Pentimalli, Ph.D. CROM – Center of Oncology Research Mercogliano, Avellino, Italy Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA

Paolo Pevarello, Ph.D. Experimental Therapeutics Programme, Centro Nacional de Investigaciones Oncologicas (CNIO), 28029 Madrid, Spain, [email protected]

Sean M. Post Department of Genetics, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA

Alfonso Quintás-Cardama Department of Genetics and Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA

Wynand P. Roos, Ph.D. Department of Toxicology, University of Mainz, D-55131 Mainz, Germany

Johannes Rudolph, Ph.DDepartment of Chemistry and Biochemistry, University of Colorado at Boulder, Boulder, CO 80309, USA, [email protected]

Zahid H. Siddik, Ph.D.Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA, [email protected]

Tom Sowin, Ph.D. Advanced Technology, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA

Ruoning Wang, Ph.D. Department of Experimental Therapeutics, Division of Cancer Medicine, M. D. Anderson Cancer Center, Houston, TX 77030, USA

Zhan Xiao, Ph.D. MedImmune, LLC, One MedImmune Way, Gaithersburg, MD 20878, USA

Heng-Yin Yang, Ph.D. Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA

Sai-Ching Jim Yeung, M.D., Ph.D. Department of Endocrine Neoplasia and Hormonal Disorders,


Contributors

xiv

Department of General Internal Medicine, Ambulatory Treatment & Emergency Care, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA

Haiying Zhang, Ph.D.Cancer Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA, [email protected]


Contributors

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