Syövät pirstaloituvat: haaste hoidon kehitykselle
Syövät pirstaloituvat: haaste hoidon kehitykselle Kimmo Porkka Professor, head of division hematology Helsinki University Central Hospital Helsinki, Finland Hematology Research Unit Helsinki Syövän heterogeenisyys: esimerkkinä akuutti myelooinen leukemia (AML) • Harvinainen sairaus; 50 potilasta/vuosi • 10-70% paranee intensiivisellä solunsalpaajahoidolla ja allogeenisella kantasolujensiirrolla • Ei täsmähoitoja (poikkeus APL) • Molekylaarinen patogeneesi tunnettu genomitasolla (2013-2014) Hematology Research Unit Helsinki AML classification in 2010 (European Leukemianet, CN) Blood 2010, Vol. 115, No. 3, pp. 453-474. Hematology Research Unit Helsinki Koko genomin/eksomin/transkriptomin sekvensointi Hematology Research Unit Helsinki AML:n genomiikka 2013 Hematology Research Unit Helsinki T. Ley ASH2012 Added complexity: within-patient, time- and therapy-dependent clonal heterogeneity Hematology Research Unit Helsinki Ding et al. Nature 2012 AML challenge for conventional drug studies 100 newly diagnosed AML patients … AML genotype 3 AML genotype 7 AML genotype 1 AML genotype 5 AML genotype 2 New drug 1: Phase I-II (n=10-40) Hematology Research Unit Helsinki AML genotype 6 AML genotype 100 AML genotype 98 Response rate 2/100= 2% AML genotype 99 Study fail End development Goal 201x AML diagnosis “Personalized therapy machine” Patient-specific drug list AML in remission Hematology Research Unit Helsinki Finnish Hematology Registry and Biobank (FHRB) Registry FHRB = + Biobank hematology.fi/fhrb Hematology Research Unit Helsinki FHRB Patient consent Sample, data collection Hospitals • 30 mL blood, 30 mL bone marrow, skin biopsy (opt.) • at diagnosis, remission (opt.), relapses • all university and central hospitals (n=21) Sample processing Finnish Red Cross Blood Service (centralized) Biobanking FAH Clinical registry FIMM Experiments, discovery Research groups Clinical applications Diagnostics Hematology Research Unit Helsinki Imaging Targeted therapies FHRB: Samples biobanked/patient Ca. 50 sample tubes/patient/sampling: all stored in LN2 Hematology Research Unit Helsinki FHRB: biobanking timeline • Started in Helsinki Dec 5, 2012; currently all newly-diagnosed and relapse patients sampled (acute leukemias, MDS, myeloma, MPN, CLL, CML) • All university hospitals (Helsinki, Turku, Tampere, Oulu, Kuopio) collecting samples, • All other hospitals treating hematological patients by the end of 2014 • Part of clinical care of the patients (453 €/sample) • 1000-1500 patients/year (50-75.000 samples/year) Hematology Research Unit Helsinki Goal 201x AML diagnosis “Personalized therapy machine” Patient-specific drug list AML in remission Hematology Research Unit Helsinki Reversing molecular drug discovery • Genome/transcriptome-driven Molecular profiling of leukemic cells Disease-associated genomic variants Molecularly targeted therapies - Rarely directly clinically actionable - 3-10+ years › Drug-response phenotype-driven Drug response profiling of leukemic cells Disease-associated drug responses - Often directly clinically actionable - Unbiased - Drug repurposing Hematology Research Unit Helsinki Molecularly dissection of drug response Molecularly targeted therapies - 1-5+ years Individualized systems medicine platform/Helsinki Sampling Methods Drug sensitivity and resistance testing (DSRT) - 664 anti-cancer agents and targeted inhibitors Results Effective drugs Resistant drugs Diagnosis Relapse 1 Relapse 2 Outcome Patient specific treatment recommendations Molecular profiling Genome Transcriptome Signalome Individualized drug combinations Database and treatment decision system Understanding drug resistance Clonal evolution, mutations, signaling Implementation and translation + Hematology Research Unit Helsinki Leukemia sample work flow FIMM DSRT 4 days Hematology Clinic FIMM Proteomics 2 days 1h 1 day NGS 3-4 weeks FHRB Sample collection • Bone marrow aspirate • Peripheral blood • Skin biopsy • Biobanking Hematology Research Unit Helsinki Sample processing • • • • Mononuclear cell separation Protein lysates DNA extraction RNA extraction Sample analysis • Drug screening • Phospho-protein analysis • Whole genome/exome sequencing • RNA sequencing DSRT reporting as waterfall plots Resistant drugs Effective drugs Hematology Research Unit Helsinki Patient example FHRB.600: - primary chemorefractory AML (failure to 3 induction regimens) DSRT AND MOLECULAR PROFILING RESULTS Hematology Research Unit Helsinki FHRB.600: DSRT and treatment response In vivo Diarrhea perineal infection Dasatinib Sunitinib RNAseq: NUP98-NSD1 fusion Hematology Research Unit Helsinki Temsirolimus After DSRT-targeted therapy At relapse, a total loss of drug sensitivity ex vivo (and in vivo) Before DSRT-targeted therapy Hematology Research Unit Helsinki Yhteenveto • Syövän patogeneesi on hyvin heterogeeninen => jako yhä pienempiin alaluokkiin => konventionaalinen lääketutkimus (Faasi I-III) vaikeaa/mahdotonta • Lähivuosina monen syövän geneettinen tausta kartoitetaan; funktionaaliseen ymmärtämiseen ja rationaaliseen lääkekehitykseen kuitenkin pidempi matka • Yksilöllistetty tutkimus ja hoito on kehityksen avain – biopankit keskeinen työkalu • Lääketeollisuudelta vaaditaan uutta ajattelutapaa ja innovaatioita lääkekehityksen nopeuttamiseksi Hematology Research Unit Helsinki Kiitokset: FHRB Hallitus Vesa Lindström Maija Itälä-Remes Sari Tiitinen Elina Honkavaara Henna Jalovaara Outi Huoponen Eeva Mainio Kimmo Pitkänen Janna Saarela Caroline Heckman Tiina Vesterinen Kyösti Sutinen Kari Aranko Olli Kallioniemi Anssi Nykänen http://www.hematology.fi/fhrb Hematology Research Unit Helsinki Kiitokset: AML personalized medicine FIMM Chemical Biology Pesonalized Cancer Medicine Evgeny Kulesskiy Caroline Heckman Jonathan Knowles Samuli Eldfors Riikka Karjalainen Jarno Kivioja Ashwini Kumar Heikki Kuusanmäki Muntasir Mamun Majumder Alun Parsons Cancer Systems Medicine Olli Kallioniemi Henrik Edgren Disha Malani John Patrick Mpindi Astrid Murumägi Päivi Östling Krister Wennerberg Tea Pemovska Laura Turunen Anna Lehto Computational Systems Biology HUCH/HruH Kimmo Porkka Mika Kontro Satu Mustjoki Erkki Elonen Hanna Koskela Mette Ilander Tero Aittokallio Emma Anderson Petteri Hintsanen Paavo Pietarinen Agnieszka Szwajda Jaakko Vartia Bhagwan Yadav Tuija Lundán Technology Center Janna Saarela Pekka Ellonen Maija Lepistö Sonja Lagström Sari Hannula Pirkko Mattila Aino Palva Hematology Research Unit Helsinki 28 28
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