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Modulation of P53 Family Proteins in the Treatment of Neuroblastoma

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Modulation of P53 Family Proteins in the Treatment of Neuroblastoma Modulation of p53 Family Proteins in the Treatment of Neuroblastoma by Jennifer Wolter A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Department of Medical Biophysics University of Toronto © Copyright by Jennifer Wolter 2013 Modulation of p53 family proteins in the treatment in neuroblastoma Jennifer Wolter Doctor of Philosophy Department of Medical Biophysics University of Toronto 2013 Abstract Neuroblastoma is the most common type of extra-cranial solid tumour in children. Additional investigation is required to fully understand the genetics and tumour biology of neuroblastoma for improvements in patient care. We explored the importance of p53 family proteins in neuroblastoma tumorigenesis and response to therapy. Despite aggressive multi-modality treatments, more than half of patients with high-risk neuroblastoma relapse, and cure after recurrence is rare. Repurposing medications already in use for other indications is a safe and expedient way to discover novel therapies for neuroblastoma. Using a high-throughput screen of FDA-approved drugs we identified the beta-adrenergic receptor antagonist propranolol and cardiac glycosides as candidate compounds to investigate for the treatment of neuroblastoma. Studies have demonstrated that propranolol and cardiac glycosides have anti-cancer effects in range of malignancies in both in vitro and epidiomologic studies. Propranolol has a well- documented safety profile in children and more recently is used to treat infants with large hemangiomas. Cardiac glycosides have a narrower therapeutic window therefore analogues were designed in an attempt to develop a more effective anti-proliferative cardiac glycoside without cardiotoxic side effects. While these drugs have disparate anti-cancer mechanisms in neuroblastoma, both classes of compounds are able to induce neuroblastoma cell death and may reveal new targets to further improve patient care. ii Acknowledgments I would like to start by thanking my supervisors Dr. Meredith Irwin and Dr. David Malkin. Their support and mentorship in and out of the laboratory have meant so much to me over the last six years. If it were not for Dr. Irwin, I would not have had the courage to pursue a Masters degree or a PhD. I will use the critical thinking and problem solving skills I developed during my studies throughout my career. I would also like to thank my advisory committee; Dr. David Kaplan and Dr. Linda Penn, who have provided exceptional guidance and insight throughout my graduate studies. I owe a debt of gratitude to Dr Joseph Lam at The University of Guelph who helped put me on the path of research. Over the course of my studies I have had the opportunity to work with a number of remarkable trainees and researchers. I would like to thank Dr. Loretta Lau who mentored me in the early stages of my research endeavors, Lynn Cheng for her constant emotional and research support, as well as the past and present Irwin lab members for their friendship and research advice that has meant so much to me. Personally, I would like to thank my parents for their endless support throughout my education and research studies. I would like to thank my husband and collaborator, Dr. Nikolaus Wolter, for his patience, encouragement and understanding. Our work together that comprised the bulk of the Chapter 3 appendix was one of the greatest challenges our marriage has faced since we put up the wallpaper. Finally, I would like to thank my friends and family. Although my long hours in the lab often prevented me from sharing many occasions with you, knowing you would be waiting with open arms and full glass of wine was a continuous source of support. iii Table of Contents Table of Contents Abstract.....................................................................................................................................................ii Acknowledgments................................................................................................................................. iii Table of Contents...................................................................................................................................iv List of Figures.........................................................................................................................................ix List of Abbreviations.............................................................................................................................. x Chapter 1 Introduction .......................................................................................................................1 1.1 Overview of Neuroblastoma ................................................................................................................ 1 1.1.1 Clinical presentation of neuroblastoma.....................................................................................................1 1.1.2 Treatment of neuroblastoma..........................................................................................................................1 1.1.3 Tumour biology and genetic characteristics of neuroblastoma ......................................................5 1.2 p53 family ................................................................................................................................................10 1.2.1 Characteristics of p53 ..................................................................................................................................... 10 1.2.2 p53 family members: p73 and p63 ........................................................................................................... 16 1.2.3 Role of p53 family proteins in Cancer..................................................................................................... 19 1.3 β-Adrenergic signalling .......................................................................................................................25 1.3.1 β-Adrenergic Receptors ................................................................................................................................. 25 1.3.2 Pharmacological agents targeting β-adrenergic receptors............................................................. 26 1.3.3 Beta-Adrenergic signalling in cancer........................................................................................................ 29 1.4 Cardiac Glycosides.................................................................................................................................31 1.4.1 Structure and Function of Cardiac Glycosides...................................................................................... 31 1.4.2 Cardiac Glycosides and Na+/K+-ATPase ................................................................................................ 32 iv 1.4.3 Cardiac glycosides and cancer therapy ................................................................................................... 35 1.5 Conclusions..............................................................................................................................................39 Chapter 2 – The role of LFS associated p53 mutations in neuroblastoma...................... 40 2.1 Abstract.....................................................................................................................................................40 2.2 Introduction ............................................................................................................................................41 2.3 Results.......................................................................................................................................................43 2.3.1 Identification of LFS- associated neuroblastoma cases.................................................................... 43 2.3.2 Neuroblastoma LFS p53 mutants are defective in target gene induction and response to chemotherapy................................................................................................................................................................ 44 2.3.4 LFS-neuroblastoma p53 mutants form complexes with TAp73................................................... 47 2.3.4 Mutant p53 increases tumorigenicity of primary neuroblastoma cells.................................... 49 2.4 Discussion ................................................................................................................................................51 2.5 Materials and methods ........................................................................................................................55 2.5.1 Cell culture, transfections and chemotherapy...................................................................................... 55 2.5.2 Plasmids................................................................................................................................................................ 55 2.5.3 Western immunoblots and immunoprecipitation.............................................................................. 56 2.5.4 Luciferase Assay ................................................................................................................................................ 56 2.5.5 Sphere and Foci formation assay ............................................................................................................... 57 Chapter 3 – Anti-tumour activity of the beta-adrenergic receptor antagonist propranolol in neuroblastoma.....................................................................................................
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