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Transforming Growth Factor-Beta in Cancer Therapy, Volume II: Cancer Treatment and Therapy (Cancer Drug Discovery and Development) PDF

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TRANSFORMING GROWTH FACTOR-B IN CANCER THERAPY, VOLUME II CANCER DRUG DISCOVERY AND DEVELOPMENT Beverly A. Teicher, PhD, SERIES EDITOR Checkpoint Responses in Cancer Therapy, edited by Cancer Chemoprevention, Volume 2: Strategies for Wei Dai, 2008 Cancer Chemoprevention, edited by Gary J. Kelloff, Cancer Proteomics: From Bench to Bedside, edited by Ernest T. Hawk, and Caroline C. Sigman, 2005 Sayed S. Daoud, 2008 Death Receptors in Cancer Therapy, edited by Wafik S. Transforming Growth Factor-B in Cancer Therapy, El-Deiry, 2005 Volume II: Cancer Treatment and Therapy, edited Cancer Chemoprevention, Volume 1: Promising Cancer by Sonia Jakowlew, 2008 Chemopreventive Agents, edited by Gary J. Kelloff, Transforming Growth Factor-B in Cancer Therapy, Ernest T. Hawk, and Caroline C. Sigman, 2004 Volume 1: Basic and Clinical Biology, edited by Proteasome Inhibitors in Cancer Therapy, edited by Sonia Jakowlew, 2008 Julian Adams, 2004 Microtubule Targets in Cancer Therapy, edited by Nucleic Acid Therapeutics in Cancer, edited by Alan M. Antonio T. Fojo, 2008 Gewirtz, 2004 Antiangiogenic Agents in Cancer Therapy, Second DNA Repair in Cancer Therapy, edited by Lawrence C. Edition, edited by Beverly A. Teicher and Lee M. Panasci and Moulay A. Alaoui-Jamali, 2004 Ellis, 2007 Hematopoietic Growth Factors in Oncology: Basic Apoptosis and Senescence in Cancer Chemotherapy and Science and Clinical Therapeutics, edited by Radiotherapy, Second Edition, edited by David A. George Morstyn, MaryAnn Foote, and Graham J. Gerwitz; Shawn Edan Holtz, and Steven Grant, 2007 Lieschke, 2004 Molecular Targeting in Oncology, edited by Howard L. Handbook of Anticancer Pharmacokinetics and Kaufman, Scott Wadler, and Karen Antman, 2007 Pharmacodynamics, edited by William D. Figg In Vivo Imaging of Cancer Therapy, edited by and Howard L. McLeod, 2004 Anthony F. Shields and Patricia Price, 2007 Anticancer Drug Development Guide: Preclinical Cytokines in the Genesis and Treatment ofCancer, edited Screening, Clinical Trials, and Approval, Second by Michael A. Caligiuri, Michael T. Lotze, and Edition, edited by Beverly A. Teicher and Paul A. Frances R. Balkwill, 2007 Andrews, 2004 Regional Cancer Therapy, edited by Peter M. Schlag and Handbook of Cancer Vaccines, edited by Michael A. Ulrike Stein, 2007 Morse, Timothy M. Clay, and Kim H. Lyerly, 2004 Gene Therapy for Cancer, edited by Kelly K. Hunt, Drug Delivery Systems in Cancer Therapy, edited by Stephan A. Vorburger, and Stephen G. Swisher, Dennis M. Brown, 2003 2007 Oncogene-Directed Therapies, edited by Janusz Rak, 2003 Deoxynucleoside Analogs in Cancer Therapy, edited by Cell Cycle Inhibitors in Cancer Therapy: Current Godefridus J. Peters, 2006 Strategies, edited by Antonio Giordano and Cancer Drug Resistance, edited by Beverly A. Teicher, 2006 Kenneth J. Soprano, 2003 Histone Deacetylases: Transcriptional Regulation and Chemoradiation in Cancer Therapy, edited by Hak Other Cellular Functions, edited by Eric Verdin, Choy, 2003 2006 Fluoropyrimidines in Cancer Therapy, edited by Youcef Immunotherapy ofCancer, edited by Mary L. Disis, 2006 M. Rustum, 2003 Biomarkers in Breast Cancer: Molecular Diagnostics Targetsfor Cancer Chemotherapy: Transcription Factors for Predicting and Monitoring Therapeutic Effect, and Other Nuclear Proteins, edited by Nicholas edited by Giampietro Gasparini and Daniel F. B. La Thangue and Lan R. Bandara, 2002 Hayes, 2006 Tumor Targeting in Cancer Therapy, edited by Michel Protein Tyrosine Kinases: From Inhibitors to Useful Page, 2002 Drugs, edited by Doriana Fabbro and Frank Hormone Therapy in Breast and Prostate Cancer, edited McCormick, 2005 by v: Craig Jordan and Barrington J. A. Furr, 2002 Bone Metastasis: Experimental and Clinical Therapeutics, Tumor Models in Cancer Research, edited by Beverly A. edited by Gurmit Singh and Shafaat A. Rabbani, Teicher, 2002 2005 Tumor Suppressor Genes in Human Cancer, edited by The Oncogenomics Handbook, edited by William J. David E. Fisher, 2001 LaRochelle and Richard A. Shimkets, 2005 Matrix Metalloproteinase Inhibitors in Cancer Therapy, Camptothecins in Cancer Therapy, edited by edited by Neil J. Clendeninn and Krzysztof Thomas G. Burke and Val R. Adams, 2005 Appelt, 2001 Combination Cancer Therapy: Modulators and Farnesyltransferase Inhibitors in Cancer, edited by Said Potentiators, edited by Gary K. Schwartz, 2005 M. Sebti and Andrew D. Hamilton, 2001 ii TRANSFORMING GROWTH FACTOR-P IN CANCER THERAPY, VOLUME II CANCER TREATMENT AND THERAPY Edited by SONIA B. JAKOWLE~ PhD Cancer Training Branch, Office ofCenters, Training and Resources, National Cancer Institute, Bethesda, MD Foreword by CARL-HENRIK HELDIN, PhD Ludwig Institute for Cancer Research, Uppsala University, Uppsala, Sweden ~\I', H P -"1\:: umana ress © 2008 Humana Press 999 Riverview Drive, Suite 208 Totowa, New Jersey 07512 All rights reserved. www.humanapress.com All rights reserved. No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording, or otherwise without written permission from the Publisher. The content and opinions expressed in this book are the sole work of the authors and editors, who have warranted due diligence in the creation and issuance of their work. The publisher, editors, and authors are not responsible for errors or omissions or for any consequences arising from the information or opinions presented in this book and make no warranty, express or implied, with respect to its contents. Due diligence has been taken by the publishers, editors, and authors of this book to assure the accuracy of the informa- tion published and to describe generally accepted practices. The contributors herein have carefully checked to ensure that the drug selections and dosages set forth in this text are accurate and in accord with the standards accepted at the time of publication. Notwithstanding, since new research, changes in government regulations, and knowledge from clinical experience relating to drug therapy and drug reactions constantly occur, the reader is advised to check the product information provided by the manufacturer of each drug for any change in dosages or for additional warnings and contra- indications. This is of utmost importance when the recommended drug herein is a new or infrequently used drug. It is the responsibility of the treating physician to determine dosages and treatment strategies for individual patients. Further, it is the responsibility of the health care provider to ascertain the Food and Drug Administration status of each drug or device used in their clinical practice. The publishers, editors, and authors are not responsible for errors or omissions or for any consequences from the application of the information presented in this book and make no warranty, express or implied, with respect to the contents in this publication. This publication is printed on acid-free paper. e ANSI Z39.48-1984 (American National Standards Institute) Permanence of Paper for Printed Library Materials. Production Editor: Michele Seugling Cover design by Nancy Fallatt For additional copies, pricing for bulk purchases, and/or information about other Humana titles, contact Humana at the above address or at any of the following numbers: Tel: 973-256-1699; Fax: 973-256-8341; or visit our Website: http://humanapress.com Photocopy Authorization Policy: Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by Humana Press, provided that the base fee of US $30.00 per copy is paid directly to the Copyright Clearance Center at 222 Rosewood Drive, Danvers, MA 01923. For those organizations that have been granted a photocopy license from the CCC, a separate system of payment has been arranged and is acceptable to Humana Press. The fee code for users of the Transactional Reporting Service is: [978-1-58829-715-0/08 $30.00]. Printed in the United States of America. 10 9 8 7 6 5 4 3 2 e-ISBN: 978-1-59745-293-9 Library of Congress Control Number: 2007931768 IN MEMORIAM All of us in the transforming growth factor-f (TGF-J3) research community were deeply saddened to learn of the death of Anita B. Roberts on May 26, 2006. Ironically, Anita died from cancer, a disease that is now closely linked to the peptide growth factor she and her colleagues discovered in the early 1980s and that will forever be associated with her name. As I reflect on her life and her contributions to science, three memories stand out that I believe illustrate the extraordinary person that Anita was. I first met Anita in Mike Sporn's office at the NCI in the summer of 1984. I was a young scientist working for a biotechnology company in the Bay Area of California. Our research team had discovered two growth factors, designated Chondrogenic Induction Factors A and B (CIF-A and CIF-B), that appeared to be highly related to a growth factor called TGF-J3 that had been recently purified and characterized by Anita. Several of my colleagues and I met with Mike and Anita to share our data with them and to discuss how we might collaborate to more clearly elucidate the relationships between TGF-J3, CIF-A, and CIF-B. Eventually we determined that CIF-A was TGF-J31 and CIF-B was TGF-J32. I clearly remember in my first meeting with Anita, her high levels of intensity, inquisitiveness, and energy. I was also struck by her scientific rigor and attention to detail. These were professional characteristics that would become hallmarks of her scientific career during the next 22 years. A second memory I have of Anita was related to a Wound Healing Society meeting we attended together in the early 1990s in Richmond, Virginia. One evening, several of us ended up in a "drinking establishment" listening to a Blue Grass band. Late in the evening, Anita and I walked back to the hotel where we were staying, when I asked her about her family, since all we ever seemed to talk about was science. Anita told me that she married her husband Bob whom she had first met when she was a freshman in high school. It was clear to me that she loved her husband and children very much and was very proud of their accomplishments. It was refreshing for me to see someone who was both successful in the pursuit of their career and, at the same time, so committed to their family life. One of my final memories of Anita was at the 2005 Keystone Symposium on TGF-J3 that Anita, Mike Sporn, and I had co-organized. Shortly after the three of us had agreed to organize the meeting, Anita was diagnosed with gastric carcinoma. I was stunned by the news and remember lying awake that night trying to imagine how Anita must feel. Given her prognosis, I thought it was unlikely she would survive the next 12 months to even attend the meeting. Much to my amazement, not only did Anita attend, but she sat with me during the entire meeting completely immersed in the science and reminiscing about how the TGF-J3 field had progressed during the past 25 years. Anita's attendance at that meeting and another TGF-J3 meeting held in San Diego in February, 2006, symbolized her incredible courage, determination, and perseverance. Anita was truly a remarkable individual. She exhibited an unusual balance of scientific brilliance and humility. She was a very caring and loving person who changed the lives of many of the people she touched. For those of us working in the field of TGF-J3, her v vi In Memoriam death is a terrible loss. On the other hand, Anita would want us to "press on," to explore the unknown and determine whether this growth factor she discovered 25 years ago is a valid therapeutic target for diseases like cancer and pathological fibrosis. This will continue to be a difficult mission, but remembering Anita's personal and professional qualities should fortify our efforts and sustain us when we are discouraged. Although Anita is no longer with us, her indomitable spirit lives on to provide us inspiration and hope. John M McPherson, PhD FOREWORD Transforming Growth Factor-B in Cancer Therapy, Volume II: Cancer Treatment and Therapy The chapters in this volume confer an abundance of knowledge about the current state of our understanding of transforming growth factor-B (TGF-B) in cancer treatment and therapy. Unlike several more traditional positive polypeptide growth factors that stim- ulate cellular proliferation, the prototypical TGF-B is now known to inhibit the growth of most normal cell types, including those of epithelial and mesenchymal origin. However, there are examples of cell types that can be stimulated by TGF-B under certain conditions. TGF-B also induces the accumulation of matrix molecules by stimulating their synthesis as well as inhibiting their degradation. Moreover, TGF-B induces apoptosis of certain cell types, thereby restricting their proliferation. Overactivity ofTGF-~ has been linked to several diseases. For instance, the effect of TGF-~ on matrix accumulation contributes to fibrotic conditions, like glomerulonephritis, lung fibrosis and liver cirrhosis (1). TGF-~ has a very complicated role in cancer that is only beginning to be understood. Initially, TGF-~ is a tumor suppressor since it inhibits the growth of most cell types and induces apoptosis. However, at later stages of tumorigenesis, TGF-~ has tumor promoting effects (2). TGF-~ is often produced at high amounts in advanced tumors and such tumor cells often acquire resistance against the growth inhibitory effects ofTGF-~. TGF-~ also induces epithelial-to-mesenchymal transition (EMT) which correlates with increased invasiveness and metastasis (3). Moreover, TGF-B has effects on normal cell types of tumors which also contribute to tumor progression; it inhibits the immune system and thereby suppresses the immune surveillance of tumors, and promotes angiogenesis which is needed for tumor growth. Importantly, high levels of TGF-B have been shown to cor- relate to poor prognosis for patients with advanced forms of breast cancer, colorectal cancer, prostate cancer and lung cancer (4). The present volume contains 46 chapters, which start with a series of 17 informative chapters that characterize the roles of TGF-~ in different types of developing and advanced cancers in detail. Next, the reader will have the opportunity to review recent exciting developments of TGF-~ in cancer treatment and therapy in a full 17 chapters. The concluding stimulating 12 chapters deal with the development of inhibitors of TGF-~ signaling for therapy and summarize the current status of this interesting and rapidly moving field of research. Thus, the reader will have an opportunity to enjoy an overview of the intriguing role ofTGF-~ in cancer treatment and therapy. The well-established tumor promoting effect of TGF-~ in advanced cancers makes TGF-~ signaling antagonists attractive targets for the development of effective drugs for the treatment of cancer patients. Possible types of TGF-~ antagonists that may be clinically useful include monoclonal antibodies against TGF-~ itself or its receptors, soluble forms of the extracellular part of the TGF-~ type II receptor, which bind and trap the ligand, and low molecular weight compounds, which inhibit the kinases of TGF-~ type I or type II receptors (1,4). The first generation of such inhibitors is now available and is being used in tumor models in animals. Some vii viii Foreword encouraging results have already been obtained and are described in some of the contributing chapters in this volume. The challenge in the attempt to use TGF-p antagonists in tumor treatment is the fact that TGF-p has both tumor suppressing and tumor promoting effects. Thus, too efficient TGF-p inhibition, which obliterates the inhibitory effect of TGF-p on cell growth and its stimulatory effect on apoptosis, could increase the risk of tumor development. This risk would be low if there is a difference in dose-dependency for the tumor promoting and tumor suppressing effects of TGF-p, and if the tumor promoting effects could be blocked by a partial inhibition of TGF-p signaling, which does not inhibit the tumor suppressive effects. Whether there is such a difference in dose-dependency remains to be explored. Alternatively, there is a need to develop more selective TGF-p antagonists that inhibit only the tumor promoting effects of TGF-p, such as EMT, while leaving the growth suppressive effects, such as growth inhibition and apoptosis, unperturbed. It is known that Smad molecules are important both for the tumor suppressive effects (growth inhibition) and tumor promoting effects (EMT) (1). However, whether it will be possible to develop inhibitors that antagonize only certain Smad interactions, but not other interactions, remains to be determined. Moreover, before efficient selective inhibitors can be developed, we need to learn more about which Smad interactions and other sig- naling pathways mediate the various effects of TGf-B (5-8). In addition, before we know whether TGF-p antagonists will be clinically useful, a lot of work remains to be done for the development and validation of suitable TGF-p antagonists. Thus, the present volume confers a feast of knowledge about recent advancements in the role of TGF-p in cancer treatment and therapy, and the reader will be treated to new developments that are likely to lead to more interesting and exciting treatment and therapy possibilities in the future. Carl-Henrik Heldin, PhD Ludwig Institute for Cancer Research, Uppsala University, Uppsala, Sweden REFERENCES 1. Laping NJ, Huet S. TGF-~ receptor kinase inhibitors for treatment of fibrosis. In: Smad signal trans- duction: Smads in proliferation, differentiation and disease. ten Dijke P and Heldin C-H, eds Springer Verlag, 2006, pp 443-459. 2. Akhurst RJ, Derynck R. TGF-beta signaling in cancer-a double-edged sword. Trends Cell Biol 2001;II:S44-S51. 3. Thiery JP. Epithelial-mesenchymal transitions in development and pathologies. CUff Opin Cell Biol 2003;15:740-746. 4. Lahn M, Berry B, Kloeker S, Yingling JM. TGF-~ receptor kinase inhibitors for the treatment of cancer. In: Smad signal transduction: Smads in proliferation, differentiation and disease. ten Dijke P and Heldin C-H, eds Springer Verlag, 2006, pp 415-442. 5. Massague J. How cells read TGF-~ signals. Nat Rev Mol Cell Bioi 2000;1:169-178. 6. Derynck R, Zhang YEo Smad-dependent and Smad-independent pathways in TGF-~ family signalling. Nature 2003;425:577-584. 7. ten Dijke P, Hill CS. New insights into TGF-~-Smad signalling. Trends Biochem Sci 2004;29:265-273. 8. Moustakas A, Heldin C-H. Non-Smad TGF-~ signals. J Cell Sci 2005;118:3573-3584. PREFACE The transforming growth factor-f (TGF-~) superfamily of secreted signaling proteins shows high conservation among eukaryotes. This superfamily is composed of proteins that regulate cell fate in development and homeostasis including tissue remodeling, histogenesis and maintenance of epithelial homeostasis. TGF-~ was originally named for its ability to induce malignant behavior of normal fibroblasts and it was proposed that TGF-~ might playa role in uncoupling a cell from normal growth control. Paradoxically, TGF-~ exhibits a ubiquitous pattern of expression in normal developing and adult tissues, and unlike most polypeptide growth factors, TGF-~ is produced by, and can act on, nearly every cell type. Numerous studies have established that the TGF-~ signaling mechanism begins with TGF-~ ligand binding to TGF-~ receptors that causes receptor serine/threonine kinases to phos- phorylate and activate receptor-regulated Smads, and/or initiate non-Smad signaling through activation of mitogen-activated protein kinases, phosphatidylinositol 3-kinase and other mediators. The receptor-regulated Smads heterooligomerize with the common Smad, Smad4, before translocating to the nucleus, where they regulate gene expression. Mutations and epigenetic dysregulation of TGF-~ signaling mechanisms occur commonly in major human diseases including cancer, fibrosis, and immune and vascular diseases. The TGF-~ signaling system controls a wide range of cellular functions that depend on cell type and physiological or patho-physiological context. In epithelial cells, TGF-~ may play several roles including inhibition of cell growth, initiation of apoptosis and induction of epithelial to mesenchymal transition. In contrast, the effects ofTGF-~ on cellular growth and apoptosis in stromal fibroblasts are minor compared with its potent ability to stimulate cell-matrix adhesion and matrix remodeling and promotion of cell motility. Elucidation of cell type- and context-dependent molecular signaling mechanisms that control the varia- tions in functional specificity of TGF-~ signaling is extremely important in understanding key processes that occur in normal development and homeostasis and how these processes change in cancer and disease. With the discovery that TGF-~ is a potent growth inhibitor of epithelial cells and the identification of inactivating mutations within the TGF-~ signaling pathway in cancer, it has become clear that the TGF-~ signaling system is a tumor suppressor pathway in early stages of cancer progression. However, many human cancers show increased expression of TGF-~ that is associated with poor patient prognosis and increased frequency of metastasis. The stage-specific duality of multifunctional TGF-~ is the emerging paradigm for the role of TGF-~ in cancer and disease and the mechanism by which the switch of TGF-~ from heroic tumor suppressor to villainous pro-oncogene occurs is the subject of intense investigation. New therapeutic opportunities may emerge from a clearer understanding of the molecular and cellular contexts that permit the tumor suppressor versus oncogenic activities of TGF-~. It has been nearly 25 years since TGF-~ was discovered and several thousand articles have been published about the role of TGF-~ in normal and tumor cells. During the same time, there has been a large increase in our understanding of TGF-~ in cancer and disease. There has also been a significant change in the general direction of therapeutics' discovery and development. Both protein therapeutics and small molecule therapeutics are now described as being molecularly targeted. It is time to review the field of TGF-~ in cancer and cancer therapy in the post-genomic, molecularly targeted era. ix

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