Oncologie in de komende periode: verbetering door selectie
Martijn P. Lolkema 7 maart 2013 Department of Medical Oncology
The Netherlands
Kanker: nog steeds een belangrijke doodsoorzaak
Oncologie 1.0
Oncologie 2.0
http://nextarchitects.com/
Hallmarks of cancer Versie 1
Versie 2
There are >900 drugs in development Only 5% of novel drugs in cancer treatment become FDA/EMA approved Success rate 100% ~60% 90
x
~30%
x
~40%
x
~70%
=
~5%
80
70 60 50 40 30 20
10 0 Phase I
Phase II
Phase III
Phases in the drug development process SOURCE: I. Kola, J. Landis “Can the pharmaceutical industry reduce attrition rates?” Nature Reviews drug discovery, „04
Registration
Overall
Enriching for genetic changes that confer sensitivity to treatment: Proof of concept !
Proof of concept ! Kwak EL, et al. N Engl J Med. 2010;363:1693-703. 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.
A “thousand dollar genome”
Wat gebeurt er als we de genetische code van het kanker DNA kunnen kraken?
Genetica voorspelt respons op therapie
Normal cell
Cancer cell with mutation Log cell survival!
Log drug concentration!
How to organize personalized cancer treatment
www.cpct.nl
•1
Biopsie pipeline CPCT
•Breast •Liver •3 specimens CPCT-02 •(+ 1 for regular diagnostics)
•Tumor percentage: 80% •DNA isolation: 10400 ng
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
Site of Biopsy
•TKI
•BRAF inhibitor
% of samples
25 20 15 10 5
•Platinum based
Li ve r ot Sk Ly he in m ph r /S n ub cu ode ta ne ou s
•Non platinum based •Smoothened inhibitor •CDK 4/6 inhibitor •Anti hormonal •Integrin antagonist •No treatment 0
2
4
6
8
Lu ng
0
Biopten succes percentage
Distribution of DNA yield
% of usefull biopsies N=65 100
75
50
no DNA <250ng >250ng but <500ng >500ng 25
0
DNA yield (ng)
% of samples
15000
10000
5000
0
500ng
Casus: BRAF mutant melanoom/ colorectaal carcinoom
Oncogen signalering: zorgt voor proliferatie
EGFRi Cell membrane
EGFR
KRAS BRAFi
BRAF MEKKi
MEKK
Proliferation
Less proliferation
Vemurafenib: initiele effectiviteit
100 75
%Change From Baseline (Sum of Lesion Size)
• Tumorrespons vond plaats in de meerderheid (81%) van patiënten in de V600+ melanoom extensie cohort (960 mg BID)
50 25 0 -25 -50 -75 -100
• Onderzoeker bepaald • Inclusief bevestigde & onbevestigde tumorrespons
BRAF inhibitor: linear pathways anyway? Cell membrane
EGFR
KRAS PI3K
Rho BRAFV600E
AKT Rac MEKK
Motility/ invasiveness
Proliferation
MTOR
Survival
Voor sommige pathways geldt dat de liniaire componenten dermate goed in kaart zijn gebracht dat de resistentie verklaard kan worden
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:10.1038/nature10868 •Note: This figure is from a near-final version AOP and may change prior to final publication in print/online
Network theorie
The question is: do linear pathways exist?
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 100-500 ng
Patient Stratification
Research
IonTorrent PGM
SOLiD 5500xl
+
Biomarker Discovery Profiling Cancer Pathways and Processes
Actionable Mutations >50-100 genes Start Targeted Therapy
Allocation Fase1 Clinical Trial
Systems Biology
Response monitoring Resistance / Progression
Recurrence / Cure
Targeted Resequencing ± 2000 genes Bioinformatic analysis
Databanking
in vitro / in vivo Modeling of Hypotheses
Mutations, INDELs, Copy Number Variations
Three Weeks
One Week
10-50 ng
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
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
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