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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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
Madison, WI, USA 100 80 60 40 20 0 1nM Max Min Blast response 10nM 100nM 1000nM CONCENTRATION (nm) Control response 10000nM sdss
Effective drugs Resistant drugs Selective DSS 25 20 15 10 5 0-5 -10-15 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-00477736 Clofarabine Idarubicin
a) b) DSS 40 30 20 10 0 CHEMOTHERAPY TARGETED AGENTS IDARUBICIN CYTARABINE VINCRISTINE RUXOLITINIB SUNITINIB TRAMETINIB PERCENTAGE OF SAMPLES 40 30 20 10 0 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 COUNT (x10e9/l ) b) sdss d) 20 10 0 PRE Dasatinib CLONE 1 CLONE 2 CLONE 3 CLONE 4 CLONE 5 POST sdss 20 10 0 PRE Sunitinib POST sdss 20 10 0 Temsirolimus PRE POST
α- FOLD CHANGE RELATIVE TO WT 40 30 20 10 0 EV WT N642H T648S I704L N642H + I704L a) b) SURVIVAL (%) 100 75 50 25 Idelalisib Temsirolimus MK-2206 SURVIVAL(%) 100 75 50 25 Navitoclax Ruxolitinib Tofacitinb 0 1nM 10nM 100nM 1000nM 10000nM 0 1nM 10nM 100nM 1000nM 10000nM CONCENTRATION CONCENTRATION
a) b) 50 P = 0.008 50 P < 0.0001 DSS VENETOCLAX 40 30 20 10 DSS NAVITOCLAX 40 30 20 10 0 0 HEALTHY DONORS AML HEALTHY DONORS AML
40 40 P = ns a) b) NAVITOCLAX sdss 30 20 10 0 sdss VENETOCLAX 30 20 10 0-10 0 10 20 30 40 VENETOCLAX sdss -10 DIAGNOSIS RELAPSE/ REFRACTORY a) b) CLL Highly sens AML Intermed AML Resistant AML Healthy donors -10 0 10 20 30 40 sdss % SURVIVAL 0 1 10 100 1000 10000 Concentration (nm) 100 75 50 25 RESISTANT HIGHLY SENSITIVE
.
a) b) AML Myeloma ALL MDS Other Plasmacell dyscrasia MPN CML Lymphoma CLL 2000 1500 1000 500 0 2012 2013 2014 2015 2016 2017 a) b) c) VIABILITY (%) 100 80 60 40 20 YIELD (µg) 15.0 12.5 10.0 7.5 5.0 2.5 RIN 10.0 7.5 5.0 2.5 0 0.0 RNA DNA 0.0 VIABILITY (%) 100 75 50 25 0 1266 3491 3795 4382 SAMPLE 4555 RIN 10.0 7.5 5.0 2.5 0.0 1266 3491 3795 4382 SAMPLE 4555 Months from sampling 6 12 18 24 30 36