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

Koko genomin/eksomin/transkriptomin sekvensointi

Hematology Research Unit Helsinki

AML:n genomiikka 2013

T. Ley ASH2012

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

Effective drugs

Resistant drugs

DSRT reporting as waterfall plots

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