Emerging Therapeutic Targets in Ovarian Cancer

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2 Emerging Therapeutic Targets in Ovarian Cancer

3 Stan Kaye Robert Brown Hani Gabra Martin Gore Editors Emerging Therapeutic Targets in Ovarian Cancer 123

4 Editors Stan Kaye Drug Development Unit Institute of Cancer Research/ Royal Marsden Hospital Sutton, SM2 5PT, UK Hani Gabra Department of Surgery and Cancer Imperial College London, W12 0NN, UK Robert Brown Department of Surgery and Cancer Imperial College London, W12 0NN, UK Martin Gore Department of Medicine Royal Marsden NHS Foundation Trust and Institute of Cancer Research London, SW3 6JJ, UK ISBN e-isbn DOI / Springer New York Dordrecht Heidelberg London Springer Science+Business Media, LLC 2011 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 (

5 Ovarian Cancer Action Ovarian Cancer Action is dedicated to advancing and supporting ovarian cancer research as part of its mission to save women s lives. It is an independent charity and funds a broad range of research to achieve: accurate and early detection more effective treatments better survival rates The Ovarian Cancer Action Research Centre The Ovarian Cancer Action Research Centre, based at Imperial College London and the Royal Marsden Hospital, is the only UK research facility entirely dedicated to ovarian cancer. This Centre is an international hub for ovarian cancer research, fast-tracking new treatments from bench to bedside. Other research funding In addition, funding is granted to other UK research institutions, hospitals and universities. Ovarian Cancer Action also organises the influential Helene Harris Memorial Trust International Forum on Ovarian Cancer and Ovarian Cancer Action International Conferences. Find out more about the pioneering work underway at the Ovarian Cancer Action Research Centre at

6 Preface Clinicians caring for advanced ovarian cancer patients are well aware of the challenges in dealing with the disease. Although it is frequently responsive to a range of conventional cytotoxic agents, it generally recurs and proves to be fatal. In facing the major obstacles to improvements in outlook non-selectivity and drug resistance the expectation today is that a better appreciation of the underlying biology and molecular pathology of the disease will translate into genuine progress in therapy. While there is still much to be understood about the different histological types of ovarian cancer, we are already seeing progress in linking the biology of ovarian cancer with novel targets and innovative therapies entering clinical trials. The purpose of this book is to provide an up-to-date perspective, in essence a progress report to date on efforts to meet these challenges. The basis of successful therapeutic developments is a partnership between laboratory-based and clinicalbased research scientists, and this is exemplified in the co-authorship of the 13 articles. We have identified those areas of translational research which we believe have shown the most promise, or are likely to do so, in the treatment of ovarian cancer. Each author has provided a background review of the biology behind his/her emerging target for therapy, followed by a comprehensive and up-to-date summary of treatment results. A theme which runs throughout the book is the importance of predictive biomarkers and the message of patient selection for novel-targeted therapy is now a familiar one in modern cancer therapy. The 13 chapters are prefaced by two introductory general contributions, describing existing treatments and the discovery of novel targets. A point sometimes made is that no sooner is a book such as this published than it is out of date. Clearly new information continues to emerge on a monthly basis, and this of course is to be applauded. But we believe that there is a role for a concise overall picture, especially vii

7 viii Preface in 2010, which is a particularly eventful year for treatment developments in ovarian cancer. As final touches to the book are made, we are learning of the positive results in GOG 218 and ICON-7, which incorporated bevacizumab into first line treatment, and of the first clinical evidence of response in sporadic ovarian cancer to single agent PARP inhibitor treatment (see Chapters 3 and 6). These, and other positive trial data, provide real hope for improvements in treatment outcome in the near future. We hope that the book will prove useful to both clinicians and non-clinicians with interests in the field of new drug development in ovarian cancer and welcome any constructive comments and criticisms. London October 2010 Stan Kaye Robert Brown Hani Gabra Martin Gore

8 Contents 1 Systemic Therapy for Ovarian Cancer, Current Treatment, Recent Advances, and Unmet Needs... 1 Susana Banerjee, Michael A. Bookman, and Martin Gore 2 Discovery of Novel Targets John Farley and Michael J. Birrer 3 Novel Anti-angiogenic Therapies in Ovarian Cancer Jurjees Hasan and Gordon Jayson 4 Targeting the AKT Pathway in Ovarian Cancer Euan A. Stronach, Azadeh Cheraghchi-Bashi, Michelle Chen, and Hani Gabra 5 Inhibition of the Src Oncogene: Therapeutic Potential in Ovarian Carcinoma Liz Y. Han and Anil K. Sood 6 Tumour-Specific Synthetic Lethality: Targeting BRCA Dysfunction in Ovarian Cancer Timothy A. Yap, Stan Kaye, Alan Ashworth, and Andrew Tutt 7 Targeting Inflammatory Pathways in Epithelial Ovarian Cancer. 133 Jermaine Coward and Frances Balkwill 8 Epithelial-to-Mesenchymal Transition and Cellular Membrane Receptors in Ovarian Cancer: Moving Forward in the Era of Molecularly Targeted Therapy Lainie P. Martin, Julia J. Perkins, and Russell J. Schilder 9 Epigenetic Therapies Robert Brown, Nadine Chapman-Rothe, and Ros Glasspool 10 Ovarian Cancer Immunology and Immunotherapy Sadaf Ghaem-Maghami and Martin Gore 11 Ovarian Cancer Progenitor/Stem Cells: Therapeutic Potential Susan K. Murphy and Andrew Berchuck ix

9 x Contents 12 Potential for α-folate Receptor-Targeted Treatment for Ovarian Cancer Chau H.M. Ng and Ann L. Jackman 13 New Insights into Tubulin Binders Carles Escriu and James D. Brenton Index

10 Contributors Alan Ashworth Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London SW3 6JB, UK, Frances Balkwill Barts and The London School of Medicine and Dentistry, Institute of Cancer, Centre for Cancer and Inflammation, Queen Mary University of London, London EC1M 6BQ, UK, Susana Banerjee Medical Oncology, The Royal Marsden Hospital, London, UK, Andrew Berchuck Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC 27708, USA, Michael J. Birrer Department of Medicine, Harvard Medical School, Massachusetts General Hospital, Boston, MA 02114, USA; Gynecologic Cancer Research Program, Dana Farber/Harvard Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Gynecologic Medical Oncology, Massachusetts General Hospital, Boston, MA 02114, USA, Michael A. Bookman Hematology-Oncology, Arizona Cancer Center, Tucson, AZ , USA, James D. Brenton CRUK Cambridge Research Institute, Li Ka Shing Centre, Cambridge CB2 0R, UK, Robert Brown Epigenetics Unit, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London W12 0NN, UK, Nadine Chapman-Rothe Epigenetics Unit, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London W12 0NN, UK, xi

11 xii Contributors Michelle Chen Department of Surgery and Cancer, Section of Molecular Therapeutics, Ovarian Cancer Action Research Centre, Imperial College London, Hammersmith Hospital, London W12 0NN, UK, Azadeh Cheraghchi-Bashi Department of Surgery and Cancer, Section of Molecular Therapeutics, Ovarian Cancer Action Research Centre, Imperial College London, Hammersmith Hospital, London W12 0NN, UK, Jermaine Coward Barts and The London School of Medicine and Dentistry, Institute of Cancer, Centre for Cancer and Inflammation, Queen Mary University of London, London EC1M 6BQ, UK, Carles Escriu CRUK Cambridge Research Institute, Li Ka Shing Centre, CB2 OR, Cambridge, UK, John Farley Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA, Hani Gabra Department of Surgery and Cancer, Section of Molecular Therapeutics, Ovarian Cancer Action Research Centre, Imperial College London, Hammersmith Hospital, London W12 0NN, UK, Sadaf Ghaem-Maghami Department of Gynaecological Oncology, Hammersmith Hospitals Trust, London W12 0HS, UK, Ros Glasspool Beatson Oncology Centre, The Beatson West of Scotland Cancer Centre, Glasgow G12 0YN, UK, Martin Gore The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, Fulham Rd, London SW3 6JJ, UK, Liz Y. Han Drug Development Unit, The Royal Marsden Hospital, London, UK, Jurjees Hasan Department of Medical Oncology, Christie Hospital, Manchester, UK, Ann L. Jackman Section of Medicine, The Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK, Gordon Jayson Department of Medical Oncology, Christie Hospital, Manchester, UK, Stan Kaye Section of Medicine The Institute of Cancer Research and the Drug Development Unit, The Royal Marsden NHS Foundation Trust, Sutton, Surrey SM2 5PT, UK, Lainie P. Martin Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA 1911, USA,

12 Contributors xiii Susan K. Murphy Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC 27708, USA, Chau H. M. Ng Section of Medicine, The Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK, Julia J. Perkins Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA 1911, USA, Russell J. Schilder Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA 1911, USA, Anil K. Sood Departments of Gynecologic Oncology and Cancer Biology, Center for RNA Interference and Non-coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX , USA, Euan A. Stronach Department of Surgery and Cancer, Section of Molecular Therapeutics, Ovarian Cancer Action Research Centre, Imperial College London, Hammersmith Hospital, London, W12 0NN, UK, Andrew Tutt Breakthrough Breast Cancer Research Unit, King s College London, School of Medicine, London SE1 9RT, UK, andrew.tutt@kcl.ac.uk Timothy A. Yap Drug Development Unit, The Royal Marsden NHS Foundation Trust, Sutton, Surrey SM2 5PT, UK; Section of Medicine, The Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK, timothy.yap@icr.ac.uk

13 Chapter 1 Systemic Therapy for Ovarian Cancer, Current Treatment, Recent Advances, and Unmet Needs Susana Banerjee, Michael A. Bookman, and Martin Gore Abstract Ovarian cancer is the second most common gynaecological malignancy and the leading cause of death from gynaecological cancer. Most women present with advanced disease with little prospect of cure. The optimal management of epithelial ovarian cancer involves a multidisciplinary approach incorporating surgical staging, cytoreduction, and platinum-based chemotherapy in appropriate patients. There has been little overall change in the incidence and mortality rates from ovarian cancer over the past three decades, but improvements in survival times and quality of life have occurred as a result of key advances in both surgical and chemotherapeutic strategies. In this introductory chapter, we summarise the existing treatments for epithelial ovarian cancer, introduce recent advances, and highlight unmet needs in the treatment of epithelial ovarian cancer. Keywords Ovarian cancer Treatment 1.1 Introduction In the USA in 2008, there were 21,650 cases of ovarian cancer and over 15,500 deaths attributed to the disease (Jemal et al., 2009). This accounts for approximately 4% of all malignancy in women. In the United Kingdom the relative incidence and mortality are similar, with 6,600 ovarian cancer diagnoses and more than 4,500 deaths (Cancer Research UK). There remains a lack of adequate diagnostic tests to detect ovarian cancer at an early stage, reflecting the underlying biology of the disease, with a propensity to disseminate within the peritoneal cavity. Many women present with advanced disease (75 80%) with little prospect of cure; the 5-year survival rate for advanced ovarian cancer is approximately 30 40%. The optimal management of epithelial ovarian cancer involves a multidisciplinary approach incorporating surgical staging, cytoreduction, and platinum-based chemotherapy in appropriate patients. There has been S. Banerjee (B) Medical Oncology, The Royal Marsden Hospital, London, UK susanabanerjee@doctors.org.uk S. Kaye et al. (eds.), Emerging Therapeutic Targets in Ovarian Cancer, DOI / _1, C Springer Science+Business Media, LLC

14 2 S. Banerjee et al. Improvements in overall survival for ovarian cancer (total population) over the decades 1970s Alkylating agents 12 months Cisplatin s Platinum agents months Carboplatin1989 Paclitaxel 1992 Topotecan 1996 PLD s Platinum with taxanes months 2000s Targeted agents?? months Gemcitabine 2006 Median survival Fig. 1.1 Improvements in overall survival for ovarian cancer (total population) over the decades. FDA approval of agents are indicated. PLD: pegylated liposomal doxorubicin little overall change in incidence and mortality rates over the past three decades, but improvements in survival times and quality of life have occurred as a result of key advances in both surgical and chemotherapeutic strategies (Fig. 1.1). Data from the Gynecologic Oncology Group (GOG) database demonstrates that over the last three decades, there has been stepwise progress in 10-year overall survival for patients with suboptimal residual disease post-surgery from 0 to 10% and more recently to 20%. For optimally debulked patients, improvements in 10-year overall survival have been from 7 to 40% (Thigpen, 2009). This reflects the introduction of platinum compounds followed by the addition of taxanes in front-line regimens for ovarian cancer together with advances in staging and cytoreductive surgery, availability of multiple cytotoxic agents to manage recurrent disease, and improvements in supportive care. There remains a significant risk of recurrence and resistance to therapy and hence there is a continued need to improve current treatment options. Over recent years, our understanding of the biology of epithelial ovarian cancer has improved considerably together with the selection of novel molecular targets. This book provides a comprehensive guide to emerging therapeutic targets in ovarian cancer. In this chapter, we summarise the existing treatments for epithelial ovarian cancer, introduce recent advances, and highlight unmet needs. 1.2 Existing Treatments for Newly Diagnosed Ovarian Cancer The clinical management of newly diagnosed ovarian cancer depends on the initial surgical staging according to the system endorsed by the International Federation of

15 1 Systemic Therapy for Ovarian Cancer 3 Gynaecologists and Obstetricians (FIGO) (Heintz et al., 2006). Tumour stage is the most important prognostic indicator of ovarian cancer. Therefore, it is imperative that complete surgical staging is achieved to assess all potential sites of spread. Optimal cytoreduction ( optimal debulking ) is defined as residual disease less than 1 cm in diameter after surgery. This is an important parameter because it is the strongest prognostic factor after stage. In addition, removal of bulky disease can improve disease-related symptoms. The importance of surgery being performed by gynaecologists specialising in oncology cannot be over emphasised Early-Stage Ovarian Cancer (I IIa) Treatment for early-stage ovarian cancer is potentially curative. Patients with earlystage disease are initially managed with surgery followed by chemotherapy in the majority of patients with the possible exception of those who have low-risk, stage I tumours. A worse prognosis has been associated with patients who present with one or more of the following: stage Ic disease, clear cell histology, high-grade (poorly differentiated) tumours, and suboptimal surgical staging (Vergote et al., 2001; Trimbos et al., 2003; NCCN guidelines). Many regard these features as indications for adjuvant chemotherapy. Two trials have examined the role of adjuvant chemotherapy: the International Collaborative Ovarian Neoplasm (ICON-1) and the Adjuvant Treatment in Ovarian Neoplasm (ACTION) trials. These trials compared platinum-based adjuvant chemotherapy with observation following surgery in early-stage ovarian cancer, and a combined analysis demonstrated a significant (8%) 5-year survival benefit favouring the adjuvant chemotherapy group. Results from a recent update of the ICON-1 trial favoured the chemotherapy group (10-year recurrence-free survival HR = 0.70; p = 0.023; overall survival HR for death = 0.74; p = 0.066) (Swart, 2007). However, there has been criticism of the ICON- 1 trial in relation to the adequacy of surgical staging and it has been suggested that benefit may only be applicable to suboptimally staged patients (Trimbos et al., 2003). This latter suggest that treatment of microscopic residual disease, i.e. understaged patients, could explain the beneficial effect seen with adjuvant chemotherapy. A recent Cochrane Review supported this contention (Winter-Roach et al., 2009). The GOG-157 trial demonstrated no significant difference in recurrence or 5-year survival with six cycles of adjuvant carboplatin/paclitaxel compared to three cycles (Bell et al., 2006). However, there was a non-significant trend for a reduction in the cumulative risk of recurrence associated with six cycles of therapy. In a retrospective subset analysis, this potential benefit appears more prominent in patients with high-grade serous tumours and in the presence of positive peritoneal cytology (Chan et al., 2010), which also is more common with serous histology, reflecting tumour biology (Chan et al., 2008). In addition, it is now apparent that early-stage ovarian cancer has a distinct biologic profile, characterised by an increased proportion of non-serous tumours, including endometrioid and clear cell histology. When patients undergo complete surgical staging and have a tumour that is limited to the ovary, the finding of clear cell histology, in itself, does not appear to carry an independent adverse prognosis