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LEE-DISSERTATION-2019.Pdf Overcoming the Protective Effect of the Bone Marrow Microenvironment by Dual FLT3 and BET Inhibition in FLT3-ITD Acute Myeloid Leukemia by Lauren Y. Lee A dissertation submitted to Johns Hopkins University in conformity with the requirements for the degree of Doctor of Philosophy. Baltimore, Maryland March 2019 © Lauren Y. Lee 2019 All rights reserved Abstract Acute myeloid leukemia (AML) develops from a block in the terminal differentiation of myeloid progenitor cells. Internal tandem duplication mutations in the juxtamembrane region of the FLT3 receptor tyrosine kinase (FLT3-ITD) are found in about one-third of AML cases and confer a poor prognosis, particularly in relapsed or refractory settings. Although FLT3 tyrosine kinase inhibitors (TKIs) have been modestly successful as a monotherapy in FLT3-ITD AML, the disease almost always progresses within a few months’ time due to the emergence of resistant clones, including those harboring tyrosine kinase domain (TKD) mutations. We characterized gilteritinib as a novel FLT3 TKI inhibitor that targets FLT3/TKD mutants with high potency and less myelosuppressive effects, as compared to other clinical FLT3 inhibitors. Even so, gilteritinib fails to overcome the protective effects of the bone marrow environment. We thus explored the dual inhibition of converging FLT3 and BET pathways to target downstream effector proteins that promote leukemia cell survival and proliferation. This study is the first to investigate the combination of FLT3 and BET inhibitors in primary AML cells modeled in a stromal microenvironment in vitro using clinical stage drugs. Our pre-clinical suggests that this regimen would be translatable to a clinical study in AML patients study with the novel combination of these two classes of drugs. Mark Levis, M.D., Ph.D. (Thesis Advisor) Gabriel Ghiaur, M.D., Ph.D. (Thesis Reader) ii Acknowledgements First and foremost, I cannot begin to express my gratitude to my thesis mentor, Mark Levis, who has an open-door policy and has given me invaluable guidance on scientific troubleshooting, my non-traditional career path, and life in general. I genuinely cannot imagine completing my PhD studies under any other advisor and can only hope that I have absorbed a small part of his vast knowledge on drug development and world history over the past four years. The former and current members of the Levis laboratory have also been instrumental in my thesis work. I am eternally grateful for Daniela Hernandez, who served as my immediate support line whenever I had experimental troubles or a bad day. I also had the pleasure of working with Triv Rajkhowa, who could always be counted on to manage laboratory needs and accomplish any given task. I would next like to thank my committee members, Gabriel “Gabe” Ghiaur, Alan Friedman, and John Isaacs, for providing insight and constructive feedback throughout my studies. Gabe and two members of his laboratory, Bogdan Paun and Laura Palau, were indispensable in developing my primary stroma models as they have always enthusiastically shared their bone marrow filters, reagents, and protocols with me. I am deeply indebted to the CMM program and my classmates, who have continuously supported me in every aspect throughout my time here at Johns Hopkins. iii Special thanks to Justina Caushi, a close friend and CMM classmate, who shared her sonicator and baked goods with me. Lastly, my academic career would not have made it this far if it were not for my family and Alex Wong, who have emotionally and financially supported me since the days of my adolescent dreams of becoming a Ph.D. scientist. iv Contents Abstract .............................................................................................................................. ii Acknowledgements .......................................................................................................... iii Contents ............................................................................................................................. v List of Tables .................................................................................................................... ix List of Figures .................................................................................................................... x Introduction ....................................................................................................................... 1 1.1 Acute Myeloid Leukemia ............................................................................... 1 1.2 FLT3 Receptor Tyrosine Kinase ..................................................................... 3 1.3 FLT3 Tyrosine Kinase Inhibitors.................................................................... 5 Methodologies .................................................................................................................... 9 2.1 Drug Procurement ......................................................................................... 10 2.1.1 FLT3 Inhibitors ..................................................................................... 10 2.1.2 BET Inhibitors ...................................................................................... 10 2.2 Cultured Cell Lines ....................................................................................... 11 2.3 Patient Samples ............................................................................................. 12 2.4 Primary Bone Marrow Stroma Culture ......................................................... 12 2.5 Primary AML Blast and Stroma Co-Culture ................................................ 13 2.6 Cytotoxicity................................................................................................... 13 2.7 Immunoblotting............................................................................................. 14 v 2.8 Colony-forming Assays of Normal Human Bone Marrow ........................... 15 2.9 FLT3 and Myc Plasma Inhibitory Activity (PIA) Assays ............................ 15 2.10 Next-generation Sequencing ..................................................................... 16 2.11 RNA Sequencing ...................................................................................... 17 2.12 Quantitative PCR ...................................................................................... 18 Characterization of Gilteritinib ..................................................................................... 19 3.1 Introduction to Gilteritinib ............................................................................ 19 3.2 FLT3 Inhibition in Cell Lines ....................................................................... 20 3.3 Estimation of In Vivo FLT3 Inhibition ......................................................... 21 3.4 Cytotoxic Effects of Gilteritinib ................................................................... 22 3.5 Effects of Gilteritinib on Hematopoiesis ...................................................... 24 3.6 Gilteritinib is an Efficacious FLT3-ITD/TKD Inhibitor ............................... 24 FLT3 TKI in the Clinic................................................................................................... 45 4.1 FDA Approval of FLT3 TKI ........................................................................ 45 4.1.1 Midostaurin ........................................................................................... 45 4.1.2 Gilteritinib ............................................................................................. 46 4.2 Limitations of FLT3 Inhibition ..................................................................... 47 4.3 Overcoming FLT3 TKI Resistance ............................................................... 48 4.4 Moving Forward with FLT3 TKI ................................................................. 50 BET Regulates Myc Transcriptome .............................................................................. 55 vi 5.1 Introduction to the BET Family .................................................................... 55 5.2 Myc as a Therapeutic Target ......................................................................... 57 5.3 BET Inhibition in Overcoming AML Resistance ......................................... 58 Dual FLT3 and BET Inhibition ..................................................................................... 59 6.1 A Prospective Synergistic Combination ....................................................... 59 6.2 PLX51107 ..................................................................................................... 60 6.3 Quizartinib .................................................................................................... 61 6.4 In vitro Characterization of PLX51107 ........................................................ 62 6.5 Estimation of In Vivo BET Inhibition ........................................................... 63 6.6 Screening for Synergy................................................................................... 64 6.7 The Intermittent Combination System .......................................................... 65 6.8 Exploring Differential Gene Expression by RNA Expression Analysis ...... 66 6.8.1 Myc ....................................................................................................... 66 6.8.2 p63 and TNF ......................................................................................... 67 6.9 Corresponding qPCR and Immunoblots ......................................................
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