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Hematology Research Unit Helsinki
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 Ding et al. Nature 2012
Added complexity: within-patient, time- and therapy-dependent clonal heterogeneity
Hematology Research Unit Helsinki
AML challenge for conventional drug studies
100 newly diagnosed AML patients
AML genotype 1
AML genotype 2
AML genotype 3 AML genotype 5
AML genotype 6
AML genotype 7 AML genotype 98
AML genotype 99
AML genotype 100 …
New drug 1: Phase I-II (n=10-40)
Response rate 2/100= 2% Study fail End development
Hematology Research Unit Helsinki
Goal 201x AML diagnosis
“Personalized therapy
machine”
Patient-specific drug list
AML in remission
Hematology Research Unit Helsinki
Registry
Biobank
+ FHRB =
Finnish Hematology Registry and Biobank (FHRB)
hematology.fi/fhrb
Hematology Research Unit Helsinki
Sample processing Finnish Red Cross Blood Service
(centralized)
Biobanking Clinical registry FIMM
FAH
Patient consent
Sample, data collection • 30 mL blood, 30 mL bone marrow, skin biopsy (opt.) • at diagnosis, remission (opt.), relapses • all university and central hospitals (n=21)
Hospitals
Experiments, discovery Research groups
Clinical applications Diagnostics Imaging Targeted therapies
FHRB
Hematology Research Unit Helsinki
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 profiling of leukemic cells
› Drug-response phenotype-driven
- Often directly clinically actionable
- Unbiased - Drug repurposing
- 1-5+ years
Disease-associated drug responses
Molecularly dissection of drug response
Molecularly targeted therapies
Hematology Research Unit Helsinki
Individualized systems medicine platform/Helsinki
Drug sensitivity and resistance testing (DSRT) - 664 anti-cancer agents and targeted inhibitors
Molecular profiling - Genome - Transcriptome - Signalome
Methods Outcome
Database and treatment decision
system
Individualized drug combinations
Understanding drug resistance
Sampling
Diagnosis
Relapse 1
Relapse 2
Implementation and translation
+
Effective drugs
Resistant drugs
Patient specific treatment recommendations
Clonal evolution, mutations, signaling
Results
Hematology Research Unit Helsinki
Leukemia sample work flow
Hematology Clinic FIMM
1 h 1 day
FHRB
DSRT 4 days
NGS 3-4 weeks
Proteomics 2 days
FIMM
Sample collection • Bone marrow aspirate • Peripheral blood • Skin biopsy
• Biobanking
Sample processing • Mononuclear cell separation • Protein lysates • DNA extraction • RNA extraction
Sample analysis • Drug screening • Phospho-protein analysis • Whole genome/exome
sequencing • RNA sequencing
Hematology Research Unit Helsinki
DSRT AND MOLECULAR PROFILING RESULTS
Patient example FHRB.600: - primary chemorefractory AML (failure to 3 induction regimens)
Hematology Research Unit Helsinki
FHRB.600: DSRT and treatment response
In vivo
Dasatinib
Sunitinib
Temsirolimus
Diarrhea perineal infection
RNAseq: NUP98-NSD1 fusion
Hematology Research Unit Helsinki
At relapse, a total loss of drug sensitivity ex vivo (and in vivo)
Before DSRT-targeted therapy
Afte
r DSR
T-ta
rget
ed th
erap
y
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
Kimmo Pitkänen Janna Saarela Caroline Heckman Tiina Vesterinen Kyösti Sutinen Olli Kallioniemi
Hallitus Vesa Lindström Maija Itälä-Remes
Kiitokset: FHRB
Sari Tiitinen Elina Honkavaara Henna Jalovaara Outi Huoponen Eeva Mainio Kari Aranko
http://www.hematology.fi/fhrb
Anssi Nykänen
Hematology Research Unit Helsinki 28 28
FIMM Pesonalized Cancer Medicine 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
HUCH/HruH Kimmo Porkka Mika Kontro Satu Mustjoki Erkki Elonen Hanna Koskela Mette Ilander Emma Anderson Paavo Pietarinen Jaakko Vartia Tuija Lundán
Chemical Biology Krister Wennerberg Evgeny Kulesskiy Tea Pemovska Laura Turunen Anna Lehto
Computational Systems Biology Tero Aittokallio Petteri Hintsanen Agnieszka Szwajda Bhagwan Yadav
Technology Center Janna Saarela Pekka Ellonen Maija Lepistö Sonja Lagström Sari Hannula Pirkko Mattila Aino Palva
Kiitokset: AML personalized medicine