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Phd Thesis – L Aslostovar Mcmaster University - Biochemistry PhD thesis – L Aslostovar McMaster University - Biochemistry DOPAMINE RECEPTOR TARGETING IN HUMAN ACUTE MYELOID LEUKEMIA PhD thesis – L Aslostovar McMaster University - Biochemistry DOPAMINE RECEPTOR TARGETING IN HUMAN ACUTE MYELOID LEUKEMIA By LILI ASLOSTOVAR, BSc, MSc A Thesis Submitted to the School of Graduate Studies In Partial Fulfillment of the Requirements For the Degree Doctor of Philosophy McMaster University ©Copyright by Lili Aslostovar, July 2017 PhD Thesis – L Aslostovar McMaster University - Biochemistry Descriptive Note Shahid Beheshti University BACHELOR OF SCIENCE (2006) Tehran, Iran (Nutritional Sciences) Stockholm University MASTER OF SCIENCE (2010) Stockholm, Sweden (Nutrition) Stockholm University MASTER OF SCIENCE (2011) Stockholm, Sweden (Molecular Life Science) TITLE: Dopamine Receptor Targeting in Acute Myeloid Leukemia AUTHOR: Lili Aslostovar SUPERVISOR: Dr. Mick Bhatia NUMBER OF PAGES: 222 ii PhD Thesis – L Aslostovar McMaster University - Biochemistry ABSTRACT Standard of care chemotherapy for acute myeloid leukemia (AML) has remained unchanged for decades and is associated with therapy failure and unsatisfactory survival rates. While several theories have been put forth to explain the issue of therapy failure in AML, their clinical relevance remains ambiguous and they have yet to advance therapy decisions. To date, the underlying basis of therapy failure remains unresolved, partly due to a lack of reliable surrogate models that authentically reflect the biology of human AML. To dissect the unique biological basis of therapy failure in a clinically- relevant system, we developed a unique patient-derived xenograft model that simulated chemotherapy regimens in vivo. Using this model, we characterized residual leukemia populations immediately after chemotherapy exposure, and monitored their longitudinal growth kinetics towards relapse. Despite the prevailing hypothesis of therapy resistance that involves leukemia stem cells (LSCs), we found that LSC pools were profoundly depleted shortly after chemotherapy, as determined by a lack of LSC-related functional and transcriptional properties. Instead, the residual leukemia cells displayed a unique transcriptional profile that emerged prior to the unrestrained regeneration phase that led to overt relapse. With the goal of identifying novel therapeutic targets, we searched for druggable gene products within the unique transcriptional signature of these leukemia regenerating cells (LRCs), which revealed a member of the dopamine receptor (DRD) family. Functionally, AML recurrence was prevented iii PhD Thesis – L Aslostovar McMaster University - Biochemistry in mice treated with DRD antagonist thioridazine (TDZ) in combination with chemotherapy. Mechanistically, DRD modulation by small molecules and immunotargeting resulted in suppression of neoplastic self-renewal towards cellular maturation, exclusively in leukemia progenitor cells with no adverse impact on healthy hematopoietic cell function. These findings provided proof-of- concept for our targeting approach and defined a novel role for the DRD pathway in human AML biology. These pre-clinical observations motivated a phase I clinical trial to evaluate the safety and efficacy of DRD antagonist TDZ in AML patients. In a cohort of older patients with relapsed/refractory AML, treatment with TDZ resulted in a reduction of leukemic blasts, predominantly in the peripheral blood. The suppressive effect of TDZ was selective to leukemia cells and was associated with patient-specific DRD expression levels. Collectively, the data presented in this thesis offer a novel perspective on human AML biology with a focus on targetable vulnerabilities of leukemia, derived from sophisticated xenograft systems and validated with clinical level data. Our findings describe a novel role for DRDs in regulating leukemic hematopoiesis and propose DRDs as a cancer- selective therapy target for AML. iv PhD Thesis – L Aslostovar McMaster University - Biochemistry ACKNOWLEDGEMENTS Firstly, I would like to thank my supervisor, Dr. Mick Bhatia for giving me a shot at this. The lab has been my home away from home, where research was one of many things I learned. I hope to express my gratitude by getting the work that you supported over the years, to the finish line. I would also like to thank my supervisory committee members, Dr. Hope and Dr. Xenocostas. Kristin, I look up to you and your work. Thank you for all the good advice. Dr. Xenocostas, we feel so fortunate to have such an engaged collaborator like yourself, giving us first- hand clinical insights. I’d also like to thank my lab family: Allison, you are a fantastic friend and an exceptional scientist! I learn something from you every day and I look forward to what #Allilison can accomplish as a team. Ryan, thank you for being my personal interpreter, for sharing your Rydeas but withholding that Ryrage. Also, a big thank you to my wonderful fellow students: Kyle, Stefo, Sarah, Deanna, Mohammed, Jenn, Wendy and Justin, awesome post-docs: Yannick, Orlando of Torino, Borhane and Terry, and a great technical team: Monica, Zoya, Marie- Pierre, Linda, Jenn and Aline. Last but not least, thank you Eva for always looking out for me and for all of your support. It has been wonderful to get to know you and to work with you all. Finally, I’d also like to thank my family for being so understanding of my constant absence and drawn-out student life. Thank you Baba Reza and Maman Soraya, your love and support means the world to me...my beautiful sister Sanaz, for taking such good care of me here... and my brother Romin, for sending me love from home. Thank you Ivan, Pedrum, Kaveh, Myrto and Shayan for being the perfect amalgamation of fun, insightful, thoughtful and reckless. Jonathan, thank you for being so patient and caring during the frenzy of these past few months, and for all the motivation you give me every day. v PhD Thesis – L Aslostovar McMaster University - Biochemistry TABLE OF CONTENTS DESCRIPTIVE NOTE…………………………………………………………ii ABSTRACT…………………………………………………………………….iii ACKNOWLEDGEMENTS…………………………………………………….v TABLE OF CONTENTS………………………………………………………vi LIST OF FIGURES AND TABLES…………………………………………..ix ABBREVIATIONS…………………………………………………………….xi CHAPTER 1: INTRODUCTION 1.1 Overview ……………………………………………………………………1 1.2 Healthy hematopoietic system ……………………………………………1 1.2.1 Discovery of hematopoietic stem and progenitor cells ……………1 1.2.2 In vitro assays of primitive hematopoietic cells ……………3 1.2.3 In vivo assays of primitive hematopoietic cells ……………………5 1.3 Neoplastic hematopoiesis in acute myeloid leukemia ……………………8 1.3.1 Epidemiology and clinical presentation ……………………8 1.3.2 WHO classification ……………………………………………9 1.3.3 Diagnosis and prognosis of AML …………………………..10 1.3.4 Clinical management of AML …………………………………..14 1.3.5 Evaluation of therapy outcomes …………………………..17 1.4 Therapeutic targeting of leukemia stem/progenitor cells …………..18 1.4.1 Cancer stem cells …………………………………………..18 1.4.2 Current theories of therapy failure in AML …………………..21 1.4.3 Clinical relevance of leukemic stem/progenitor cells …………..24 1.4.4 Preclinical models of AML …………………………….…….27 1.4.5 Leukemia stem/progenitor cell targeting in the clinic …………..30 1.5 Dopamine receptors in hematopoiesis …………………………………..32 1.5.1 Dopamine receptor function, classification and structure …..32 1.5.2 Dopamine receptor signaling …………………………………..35 1.5.3 Dopamine receptor biology in human hematopoiesis …………..36 1.6 SUMMARY OF INTENT…………………………………………………39 Figures……………………………………………………………………….....45 CHAPTER 2: Reoccurrence of human AML disease develops from a state of therapeutic vulnerability ………………………………………………….49 Preface ………………………………………………………….49 Abstract ………………………………………………………….52 Main ………………………………………………………………….53 vi PhD Thesis – L Aslostovar McMaster University - Biochemistry Acknowledgements ……………………………………………….....64 Methods ………………………………………………………….65 References ………………………………………………………….72 Figures and Tables ………………………………………………….75 CHAPTER 3: Dopamine receptor targeting with thioridazine allows selective suppression of progenitor activity in human myeloid leukemia ………………………………………………………………………….91 Preface ………………………………………………………….91 Abstract ………………………………………………………….95 Introduction ………………………………………………………….96 Methods ………………………………………………………….97 Results …………………………………………………………104 TDZ selectively suppresses leukemic progenitor capacity …104 TDZ inhibits leukemic clonogenicity through induction of cellular maturation …………………………………………………106 Dopamine receptors are preferentially expressed in leukemic primitive cells …………………………………………………108 TDZ-induced selective suppression of leukemic progenitor cells is mediated by dopamine receptors ………………………….109 A functional DRD circuitry exists in human AML and mediates TDZ-induced suppression of leukemic clonogenicity ….111 Direct DRD1 targeting affords selective suppression of leukemic progenitors ………………………………………………….113 TDZ as a monotherapy alleviates peripheral leukemic burden in a subset of relapsed/refractory AML patients in a DRD2-dependant manner ………………………………………………….116 Discussion ………………………………………………………….118 Acknowledgements ………………………………………………….120 References ………………………………………………………….122 Figures and tables ………………………………………………….127 CHAPTER 4: A phase I clinical trial evaluating oral thioridazine in combination with intermediate dose cytarabine in acute myeloid leukemia patients 55 years of age and older with relapsed/refractory disease ………………………………………………………………………….146 Preface ………………………………………………………….146 Abstract ………………………………………………………….148
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