Oncologie in de komende periode: verbetering door selectie

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1 Oncologie in de komende periode: verbetering door selectie Martijn P. Lolkema 7 maart 2013 Department of Medical Oncology The Netherlands

2 Kanker: nog steeds een belangrijke doodsoorzaak

3 Oncologie 1.0

4 Oncologie 2.0

5 Hallmarks of cancer Versie 1 Versie 2

6 There are >900 drugs in development Only 5% of novel drugs in cancer treatment become FDA/EMA approved Success rate 100% ~60% x ~30% x ~40% x ~70% = ~5% 0 Phase I Phase II Phase III Registration Overall Phases in the drug development process SOURCE: I. Kola, J. Landis Can the pharmaceutical industry reduce attrition rates? Nature Reviews drug discovery, 04

Phase II Phase III Registration Overall Phases in the drug development process SOURCE: I.

7 Enriching for genetic changes that confer sensitivity to treatment: Proof of concept!

8 Proof of concept! Kwak EL, et al. N Engl J Med. 2010;363: Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. After screening tumor samples from approximately 1500 patients with non small-cell lung cancer for the presence of ALK rearrangements, we identified 82 patients with advanced ALK-positive disease The overall response rate was 57%; 27 patients (33%) had stable disease. A total of 63 of 82 patients (77%) were continuing to receive crizotinib at the time of data cutoff, and the estimated probability of 6-month progression-free survival was 72%, with no median for the study reached.

patients with advanced ALK-positive disease The overall response rate was 57%; 27 patients (33%) had stable disease.

9 A thousand dollar genome Wat gebeurt er als we de genetische code van het kanker DNA kunnen kraken?

10 Genetica voorspelt respons op therapie Normal cell Cancer cell with mutation Log cell survival! Log drug concentration!

11 How to organize personalized cancer treatment

12 1

13 Biopsie pipeline CPCT Breast Liver 3 specimens CPCT-02 (+ 1 for regular diagnostics) Tumor percentage: 80% DNA isolation: ng

14 % of samples Biopten naar tumor types en orgaan CRC RCC Sarcoma NET Melanoma eye Carcinoid Upper GI Head/Neck HCC Cystic adenoid Cervix Myoepithelial Melanoma Gallbladder Head/Neck Ovarian CRC CRC Breast Pancreatic CRC CRC Endometrial Breast Head/Neck Vulva RCC CRC Platinum based Smoothened inhibitor CDK 4/6 inhibitor Anti hormonal Integrin antagonist No treatment BRAF inhibitor Non platinum based TKI Liver Site of Biopsy other Lymphnode Skin / Subcutaneous Lung

Head/Neck Vulva RCC CRC Platinum based Smoothened inhibitor CDK 4/6 inhibitor Anti hormonal Integrin antagonist No

15 % of samples DNA yield (ng) Biopten succes percentage % of usefull biopsies Distribution of DNA yield 100 N= no DNA <250ng >250ng but <500ng >500ng ng

of DNA yield 100 N=65 75 15000 50 25 no DNA

16 Casus: BRAF mutant melanoom/ colorectaal carcinoom

17 Oncogen signalering: zorgt voor proliferatie EGFRi Cell membrane EGFR KRAS BRAF MEKK BRAFi MEKKi Proliferation Less proliferation

18 %Change From Baseline (Sum of Lesion Size) Vemurafenib: initiele effectiviteit Tumorrespons vond plaats in de meerderheid (81%) van patiënten in de V600+ melanoom extensie cohort (960 mg BID) Onderzoeker bepaald Inclusief bevestigde & onbevestigde tumorrespons

patiënten in de V600+ melanoom extensie cohort (960 mg BID) 100 75 50 25

19 BRAF inhibitor: linear pathways anyway? Cell membrane EGFR Rho Rac KRAS BRAFV600E MEKK PI3K AKT MTOR Motility/ invasiveness Proliferation Survival Voor sommige pathways geldt dat de liniaire componenten dermate goed in kaart zijn gebracht dat de resistentie verklaard kan worden

Motility/ invasiveness Proliferation Survival Voor sommige pathways

20 EGFR and BRAF(V600E) inhibitors synergize to induce apoptosis of CRC cells and to suppress CRC tumour growth in a xenograft model. A Prahallad et al. Nature 000, 1-5 (2012) doi: /nature10868 Note: This figure is from a near-final version AOP and may change prior to final publication in print/online

21 Network theorie The question is: do linear pathways exist?

22 One Week Three Weeks Het CPCT wil de toekomst van persoonlijke behandeling in Nederland vormgeven Center for Personalized Cancer Treatment Patient with Metastatic Disease 2-4 Biopsies Pathological Analysis DNA Isolation ng ng Patient Stratification IonTorrent PGM Research SOLiD 5500xl + Biomarker Discovery Actionable Mutations > genes Profiling Cancer Pathways and Processes Start Targeted Therapy Allocation Fase1 Clinical Trial Systems Biology Targeted Resequencing ± 2000 genes Response monitoring Bioinformatic analysis Resistance / Progression Recurrence / Cure Databanking Mutations, INDELs, Copy Number Variations in vitro / in vivo Modeling of Hypotheses

23 Conclusies De toekomst van de oncologische behandeling ligt in betere selectie voor therapie Kanker is een grote verzameling zeldzame ziektes: dus samenwerken is essentieel Genetica is de eerste stap op weg naar goede patiënt selectie Het CPCT is een platform om deze ontwikkelingen voor de Nederlandse patiënt beschikbaar te maken

24 Acknowledgments UMC Utrecht and Hubrecht laboratory, Utrecht Cuppen group Ies Nijman Wigard Kloosterman UMC Utrecht: Emile Voest Paul van Diest Maurice van den Bosch Marco Koudijs Sjoerd Elias Geert Cirkel Christa Gadellaa Marlous Hoogstraat Nicolle Besselink Stef van Lieshout EMC/Daniel den Hoed Rotterdam Stefan Sleijfer Ron Mathijsen John Martens Jacqueline Kloth NKI/AvL Amsterdam Rene Bernards Lodewyk Wessels Jan Schellens Neeltje Steeghs Nienke Lankheet Team science: andere academische centra gaan binnenkort aansluiten Logo Nuts-Ohra

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