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Drug Repurposing for the Treatment of Acute Myeloid Leukaemia with Adverse Prognosis

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Drug Repurposing for the Treatment of Acute Myeloid Leukaemia with Adverse Prognosis PhD degree in Systems Medicine (curriculum in Molecular Oncology) European School of Molecular Medicine (SEMM), University of Milan and University of Naples “Federico II” Settore disciplinare: MED/04 Drug repurposing for the treatment of acute myeloid leukaemia with adverse prognosis Debora Valli IEO, Milan Matricola n. R11470 Supervisor: Prof. Pier Giuseppe Pelicci IEO, Milan Added Supervisor: Prof. Myriam Alcalay IEO, Milan Anno accademico 2018-2019 2 Table of contents List of abbreviations ............................................................................................................ 7 Figures index ...................................................................................................................... 13 Tables index ........................................................................................................................ 17 Abstract ............................................................................................................................... 19 1 Introduction ................................................................................................................ 21 1.1 Acute myeloid leukaemia (AML) ......................................................................... 21 1.1.1 Molecular landscape of AML ........................................................................ 21 1.1.2 FLT3- tyrosine kinase receptor in AML ........................................................ 23 1.1.3 Current treatments for AML .......................................................................... 30 1.1.4 Emerging therapeutic drugs for AML: FLT3 inhibitors ................................ 33 1.2 Drug repurposing ................................................................................................... 36 1.2.1 Advantages and limitations ............................................................................ 36 1.2.2 Different approaches used for drug repurposing ............................................ 38 1.2.3 High-throughput screenings and data analysis ............................................... 39 1.2.4 Hit identification ............................................................................................ 41 1.2.5 Examples of repurposed drugs in AML ......................................................... 42 1.3 Endoplasmic reticulum stress and unfolded protein response ............................... 44 1.3.1 Adaptive UPR mechanism ............................................................................. 44 1.3.2 Chronic ER stress and transition to apoptosis ................................................ 48 1.3.3 ER stress and cancer....................................................................................... 50 2 Aim of the work .......................................................................................................... 55 3 Materials and methods .............................................................................................. 57 3.1 Cell lines ................................................................................................................ 57 3.2 Chemical and Reagents ......................................................................................... 57 3.3 Cell viability assay ................................................................................................ 58 3.3.1 First high-throughput screening ..................................................................... 59 3 3.3.2 Second screening ........................................................................................... 60 3.3.3 Dose-response curves .................................................................................... 61 3.3.4 In vitro proliferation ...................................................................................... 62 3.4 Colony formation .................................................................................................. 62 3.5 Combination treatments ........................................................................................ 63 3.6 Cell cycle analysis ................................................................................................. 64 3.6.1 Bromodeoxyuridine (BrdU) staining ............................................................. 64 3.7 Immunoblotting ..................................................................................................... 65 3.8 Thioredoxin reductase assay ................................................................................. 66 3.9 RNA extraction and reverse transcription ............................................................. 67 3.10 DNA amplification through polymerase chain reaction ....................................... 68 3.11 Agarose gel electrophoresis .................................................................................. 69 3.12 Real time PCR ....................................................................................................... 69 3.13 In vivo experiments ............................................................................................... 71 3.13.1 Toxicity study ................................................................................................ 71 3.13.2 Xenograft mouse model ................................................................................. 72 3.14 Statistical analysis ................................................................................................. 74 4 Results ......................................................................................................................... 75 4.1 First high throughput screening: setting the experimental conditions .................. 75 4.2 First high-throughput drug screening to identify compounds that inhibit growth of AML cells expressing FLT3-ITD .................................................................................... 78 4.3 Second screening: setting the experimental condition .......................................... 81 4.4 Second screening to identify compounds that preferentially inhibit the growth of FLT3 mutated cells .......................................................................................................... 84 4.5 Auranofin and pyrvinium pamoate cause loss of viability of AML cells ............. 86 4.6 The efficacy of treatment with selected-drugs combined with agents used in standard AML therapy ..................................................................................................... 90 4.7 The effect of auranofin and pyrvinium pamoate in xenograft mouse model ........ 95 4.8 Auranofin and pyrvinium pamoate induce a delay in cell cycle progression ..... 101 4 4.9 Auranofin and pyrvinium pamoate: confirming known mechanism of action.... 105 4.10 FLT3 receptor is not inhibited by auranofin and pyrvinium pamoate treatment 109 4.11 Auranofin and pyrvinium pamoate modulate ER stress and UPR ...................... 110 5 Discussion and future directions ............................................................................. 117 References ......................................................................................................................... 125 6 Appendix ................................................................................................................... 135 6.1 Cell-therapy using extracellular vesicles isolated from genetically-engineered cell lines expressing the transmembrane TNF-Related Apoptosis-Inducing Ligand (mTRAIL) ...................................................................................................................... 135 References ......................................................................................................................... 147 Publications arising from work during my PhD studentship not directly related to these projects .................................................................................................................... 149 5 6 List of abbreviations 4E-BP1 Eukaryotic translation initiation factor 4E binding protein 1 ADMET Absorption, distribution, metabolism, excretion, toxicity ALL Acute lymphoblastic leukaemia AML Acute myeloid leukaemia APC Adenomatous polyposis coli APL Acute promyelocytic leukaemia Ara-C Cytosine arabinoside (cytarabine) ASK1 Apoptosis signal-regulating kinase 1 ASXL1-2 ASXL transcriptional regulator 1-2 ATCC American Type Culture Collection ATF4 Activating transcription factor 4 ATF6 Activating transcription factor 6 ATP Adenosine triphosphate ATRA All-trans retinoic acid BAD BCL2 associated agonist of cell death BAK BCL2 antagonist/killer 1 BAX BCL2 associated X BCL-2 B-cell lymphoma 2 BCL-xL B-cell lymphoma-extra large BIM BCL-2-like protein 11 BiP Binding immunoglobulin protein BM Bone marrow BrdU Bromodeoxyuridine CEBPA CCAAT/enhancer-binding protein alpha CHOP C/EBP-homologous protein CI Combination index CK1α Casein kinase 1 alpha CLL Chronic lymphocytic leukaemia CML Chronic myelogenous leukaemia CN Cytogenetically normal CR Complete morphological remission CSF1R Colony stimulating factor 1 receptor CTG CellTiter-Glow 7 DMSO Dimethylsulfoxide DNA Deoxyribonucleic acid DNAJB9 DnaJ heat shock protein family (Hsp40) member B9 DNAJC3 DnaJ heat shock protein family (Hsp40) member C3 DNTM3A DNA methyltransferase 3 alpha DTNB 5,5′-dithiobis (2-nitrobenzoic) acid DTT Dithiothreitol DUBs Deubiquitinases E2F1 E2F transcription factor 1 E2F7 E2F transcription factor 7 ECL Enhanced chemiluminescence EDEM1 ER degradation Enhancing alpha-mannosidase
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