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Introduction to Ovarian Cancer

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Introduction to Ovarian Cancer Oncolytic Virus Therapy in Combination with Chemotherapy for Ovarian Cancer DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Chelsea M. Bolyard, B.A. Biomedical Sciences Graduate Program The Ohio State University 2013 Dissertation Committee: Dr. Balveen Kaur, Adviser Dr. Douglas McCarty Dr. Pravin Kaumaya Dr. Robert Munson Jr. Copyright by Chelsea M. Bolyard 2013 Abstract Purpose. Novel therapeutic regimens are needed to improve dismal outcomes associated with late-stage ovarian cancer. Oncolytic viruses have shown efficacy against ovarian cancer. We studied the application of an oncolytic herpes simplex virus expressing two anti-tumor genes: ICP34.5 under the stem cell- specific nestin promoter, and anti-angiogenic molecule Brain-specific Angiogenesis Inhibitor-1 (BAI1) under the strong viral promoter IE4/5 for use against ovarian cancer. We also studied the use of this viral vector in combination with a second-line standard of care chemotherapeutic drug, doxorubicin. Experimental Design. The 34.5 Expressing Nestin-driven Vasculostatin-120 Expressing (34.5ENVE) virus was tested for treatment of ovarian cancer in vitro and in vivo. Efficacy of the virus, and its antiangiogenic effects on endothelial cells were assessed in vitro in cancer cell lines and in primary patient ascites samples. Scope of cytotoxic interactions between 34.5ENVE and chemotherapeutic agent doxorubicin were evaluated using Chou-Talalay synergy analysis. Efficacy of oncolytic viral therapy in combination with doxorubicin was evaluated in vivo in the murine xenograft model of progressive human ovarian cancer. ii Results. 34.5ENVE showed robust efficacy against ovarian cancer cell lines, and even greater efficacy against ex vivo mouse and patient ascites. When combined with doxorubicin, 34.5ENVE killed synergistically with a robust increase in caspase-3/7 cleavage. The combination of doxorubicin and 34.5ENVE significantly prolonged survival in nude mice bearing intraperitoneal ovarian cancer tumors. Conclusions. This study establishes the potential for use of oncolytic HSV in combination with doxorubicin for the treatment of late-stage ovarian cancer. iii Acknowledgements I dedicate this document to my support team throughout many years, with very special thanks to my adviser, Dr. Balveen Kaur, and the members of my committee, Drs. McCarty, Munson and Kaumaya. iv Vita September 19, 1984…………………………………………….Born, Indianapolis, IN 2002……………………………………...Broad Ripple High School, Indianapolis, IN 2006……………………………….B.A. Microbiology, Miami University, Oxford, OH 2006…………………………………….B.A. Zoology, Miami University, Oxford, OH 2006 to present ………………………………………Graduate Research Associate, Biomedical Science Graduate Program, Ohio State University, Columbus, OH Field of Study Major Field: Biomedical Science Graduate Program Publications “The Role of BAI1 in Cancer and Inflammation.” Review. In preparation. “Oncolytic Virus Therapy in Combination with Chemotherapy for Ovarian Cancer.” In preparation. v Table of Contents Abstract ........................................................................................................................... ii Acknowledgements ........................................................................................................ iv Vita .................................................................................................................................. v Table of Contents ........................................................................................................... vi List of Tables .................................................................................................................. ix List of Figures ................................................................................................................. 1 Introduction .................................................................................................................... 1 Chapter 1: Introduction to Ovarian Cancer ....................................................................10 Incidence, Risk Factors, and Morbidity & Mortality .....................................................10 Ovary Structure & Function ........................................................................................12 Pathology & Site of Origin ..........................................................................................15 Theories of Disease Origination .................................................................................16 Molecular Genetics of Disease...................................................................................22 Conclusion .................................................................................................................24 Chapter 2. Ovarian Cancer Stem Cells ..........................................................................25 Ovarian Cancer Stem Cell Markers ............................................................................28 Inflammation and Cancer Stem Cells .........................................................................36 vi Conclusion .................................................................................................................38 Chapter 3: Ovarian Cancer and Metastasis ...................................................................39 Epithelial-Mesenchymal Transition .............................................................................41 Conclusion .................................................................................................................45 Chapter 4: Ovarian Cancer and Angiogenesis ...............................................................46 Ascites .......................................................................................................................47 VEGF ligand & VEGF receptor ...................................................................................48 VEGF Signaling Pathway ...........................................................................................49 Thrombospondins as anti-angiogenic agents .............................................................50 Brain Angiogenesis Inhibitor-1 (BAI1) ........................................................................52 Antiangiogenic Agents being used to treat Ovarian Cancer. ......................................54 Conclusion .................................................................................................................59 Chapter 5: Oncolytic Viral Therapy ................................................................................60 Oncolytic Viral Therapy for Ovarian Cancer ...............................................................62 Oncolytic Viral Therapy with Anti-Angiogenic Agents .................................................67 Conclusion .................................................................................................................68 Chapter 6. Combining Oncolytic Viral Therapy with Doxorubicin to Treat Ovarian Cancer ......................................................................................................................................70 Abstract .....................................................................................................................70 Translational Relevance. ............................................................................................71 vii Introduction. ...............................................................................................................72 Materials & Methods ..................................................................................................74 Results .......................................................................................................................80 Figures & Tables. .......................................................................................................87 Discussion. ................................................................................................................99 Conclusion ............................................................................................................... 104 References .................................................................................................................. 106 viii List of Tables Table 1. CD133 and Aldehyde Dehydrogenase expression in ovarian cancer stem cells. ......................................................................................................................................29 Table 2. CD44 and CD117 expression in ovarian cancer stem cells. .............................31 Table 3. CD24 expression in ovarian cancer stem cells. ................................................33 Table 4. Anti-angiogenic agents in Phase I clinical trials for use against ovarian cancer. ......................................................................................................................................56 Table 5. Phase II-III clinical trials combining antiangiogenic agents with chemotherapy for use against ovarian cancer. ......................................................................................58 Table 6. Pre-clinical studies using oncolytic viruses against ovarian cancer. .................63 Table 6, continued. ........................................................................................................64 Table 7.Clinical trials utilizing oncolytic virus for ovarian cancer
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