INDIVIDUALIZING THERAPY FOR ACUTE LEUKEMIA

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Θαδδαῖος Λύκος
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1 Hematology Research Unit Helsinki University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center Department of Hematology Helsinki, Finland Doctoral Programme in Clinical Research INDIVIDUALIZING THERAPY FOR ACUTE LEUKEMIA Mika Kontro Academic dissertation To be presented, with the permission of the Faculty of Medicine, University of Helsinki, for public examination in Biomedicum Lecture Hall 2, Haartmaninkatu 8, Helsinki, on the 8 th of September 2017, at 12 o clock noon. Helsinki 2017

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33 a) b) Total=525 Chemothreapy (n=74) Kinase inhibitor (n=262) Differentiating/ epigenetic modifier (n=61) Apoptotic modulator (n=22) Immunomodulatory (n=14) Rapalogs (n=5) HSP inhibitor (n=9) Kinesin inhibitor (n=3) Metabolic modifier (n=17) Hormone therapy (n=22) Nonsteroidal anti-inflammatory drug (n=2) Other (n=34) Total=525 Approved (n=156) Investigational (n=279) Probe (n=90) of the current drug library. Inc., Waltham, MA, USA

34 Madison, WI, USA nM Max Min Blast response 10nM 100nM 1000nM CONCENTRATION (nm) Control response 10000nM sdss

40 Effective drugs Resistant drugs Selective DSS Entinostat Refametinib Vorinostat Panobinostat Pimasertib NVP-AUY922 Selumetinib BIIB021 Prima-1 Met Navitoclax Alvespimycin Trametinib Ruxolitinib Tanespimycin Azacitidine Lestaurtinib CUDC-101 SNS-032 Dexamethasone Ponatinib Amonafide Teniposide Paclitaxel Fingolimod Gemcitabine Topotecan Etoposide Saracatinib Alisertib Obatoclax Docetaxel Vinblastine Danusertib Vinorelbine YM155 Mitoxantrone Camptothecin PF Clofarabine Idarubicin

41 a) b) DSS CHEMOTHERAPY TARGETED AGENTS IDARUBICIN CYTARABINE VINCRISTINE RUXOLITINIB SUNITINIB TRAMETINIB PERCENTAGE OF SAMPLES DASATINIB SUNITINIB TRAMETINIB TEMSIROLIMUS FORETINIB RUXOLITINIB DACTOLISIB MK-2206 SORAFENIB QUITZARTINIB

a) BM BLAST COUNT (%) 60 40 20 c) 0 0 20 40 sdss NEUTROPHILS BLASTS DAS - SUN - TEM 20 15 10 5 0-5 DAS - SUN -10 PRE POST TREATMENT TREATMENT 3 2 1 0 NEUTROPHIL

45 a) BM BLAST COUNT (%) c) sdss NEUTROPHILS BLASTS DAS - SUN - TEM DAS - SUN -10 PRE POST TREATMENT TREATMENT NEUTROPHIL COUNT (x10e9/l ) b) sdss d) PRE Dasatinib CLONE 1 CLONE 2 CLONE 3 CLONE 4 CLONE 5 POST sdss PRE Sunitinib POST sdss Temsirolimus PRE POST

47 α- FOLD CHANGE RELATIVE TO WT EV WT N642H T648S I704L N642H + I704L a) b) SURVIVAL (%) Idelalisib Temsirolimus MK-2206 SURVIVAL(%) Navitoclax Ruxolitinib Tofacitinb 0 1nM 10nM 100nM 1000nM 10000nM 0 1nM 10nM 100nM 1000nM 10000nM CONCENTRATION CONCENTRATION

49 a) b) 50 P = P < DSS VENETOCLAX DSS NAVITOCLAX HEALTHY DONORS AML HEALTHY DONORS AML

50 40 40 P = ns a) b) NAVITOCLAX sdss sdss VENETOCLAX VENETOCLAX sdss -10 DIAGNOSIS RELAPSE/ REFRACTORY a) b) CLL Highly sens AML Intermed AML Resistant AML Healthy donors sdss % SURVIVAL Concentration (nm) RESISTANT HIGHLY SENSITIVE

52 .

54 a) b) AML Myeloma ALL MDS Other Plasmacell dyscrasia MPN CML Lymphoma CLL a) b) c) VIABILITY (%) YIELD (µg) RIN RNA DNA 0.0 VIABILITY (%) SAMPLE 4555 RIN SAMPLE 4555 Months from sampling

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