Upload
james-evans
View
218
Download
0
Tags:
Embed Size (px)
Citation preview
CEA
CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRDARIIS EFS INERIS INSTITUT CURIE INSTITUT MINES-TELECOM UNICANCERIRBA IRSNCIRAD
FONDATION MERIEUX
1
ITMO Cancer
From Precision to Personalised Medicine
Brussels 24/09/2013
CEA
CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRDARIIS EFS INERIS INSTITUT CURIE INSTITUT MINES-TELECOM UNICANCERIRBA IRSNCIRAD
FONDATION MERIEUX
CEA
CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRDARIIS EFS INERIS INSTITUT CURIE INSTITUT MINES-TELECOM UNICANCERIRBA IRSNCIRAD
FONDATION MERIEUX
Genomics in Oncology: from biology to care
Generating information about cancer development and metastasis
Identifying new genes susceptible to induce « addiction », thus « targetable »
Helping to develop new therapies Helping to accelerate new drug approval: new
early phase trials, shortening time to MA
2
CEA
CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRDARIIS EFS INERIS INSTITUT CURIE INSTITUT MINES-TELECOM UNICANCERIRBA IRSNCIRAD
FONDATION MERIEUX
How are we currently using genomics in patient management?
3
Single Gene Alteration Multiple gene alterations
Already incorporated in patient management
Impacts the following decisions :
• Selection of agents:− Positive effect− Negative effect
• Prediction of toxicity• Treatment changes in
case of resistance
Under investigation at many institutions
Should it be incorporated in routine care (when?) or remain a research tool?
Is it practical?What is the cost/benefit?
CEA
CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRDARIIS EFS INERIS INSTITUT CURIE INSTITUT MINES-TELECOM UNICANCERIRBA IRSNCIRAD
FONDATION MERIEUX
Structures and Infrastructures: Molecular genetic centers
4
High quality molecular testing, all patients, anywhere in France
Partnerships between University hospitals and cancer centers
Regional organization
PPPs with Roche,
Amgen, Pfizer, GSK, AZ
High quality molecular testing, all patients, anywhere in France
Partnerships between University hospitals and cancer centers
Regional organization
PPPs with Roche,
Amgen, Pfizer, GSK, AZ
CEA
CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRDARIIS EFS INERIS INSTITUT CURIE INSTITUT MINES-TELECOM UNICANCERIRBA IRSNCIRAD
FONDATION MERIEUX
From genetic centers to biology driven therapy
5
F Nowak, JC Soria and F Calvo, Nat Rev Clin Oncol. 2012
CEA
CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRDARIIS EFS INERIS INSTITUT CURIE INSTITUT MINES-TELECOM UNICANCERIRBA IRSNCIRAD
FONDATION MERIEUX
An increasing number of actionable molecular alterations
6
PF 02341066MetiALK
CC-223LKB1iLKB1 or STK11
BKM120Pi3KiPTEN
ARQ197Crizotinib
METiMET mut/ampl
FGFR mut/ampl
PI3KCA1 or PDPK1
NRAS
HER2 mut/ampl
BRAF V600E
KRAS mut
Druggable Target
AZD4547FGFRi
PF-04691502BKM120
Pi3KiPi3Ki
PF-04691502 GSK1120212
Pi3KiMEKi
PF-00299804BIBW2992
HER2i
GSK2118436 PF-04691502
RAFiPi3Ki
GSK1120212 PF-04691502
MEKiPi3Ki
DrugClass
PF 02341066MetiALK
CC-223LKB1iLKB1 or STK11
BKM120Pi3KiPTEN
ARQ197Crizotinib
METiMET mut/ampl
FGFR mut/ampl
PI3KCA1 or PDPK1
NRAS
HER2 mut/ampl
BRAF V600E
KRAS mut
Druggable Target
AZD4547FGFRi
PF-04691502BKM120
Pi3KiPi3Ki
PF-04691502 GSK1120212
Pi3KiMEKi
PF-00299804BIBW2992
HER2i
GSK2118436 PF-04691502
RAFiPi3Ki
GSK1120212 PF-04691502
MEKiPi3Ki
DrugClass
Implementation of Next Generation Sequencing (NGS) for clinical use Development of pharmacogenetics for reducing toxicities and improving efficacy
Implementation ongoing for the investigation of a panel of genes Next years : analysis of whole exome or genome
CEA
CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRDARIIS EFS INERIS INSTITUT CURIE INSTITUT MINES-TELECOM UNICANCERIRBA IRSNCIRAD
FONDATION MERIEUX
7
New technologies… have resulted in > 100,000-fold decreases in sequencing costs:• $1,000/genome will soon be achieved
2000 2010 2015
Single genesGene panels
ExomesWhole genomes
Gene expression profiles Copy Number Variation
CEA
CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRDARIIS EFS INERIS INSTITUT CURIE INSTITUT MINES-TELECOM UNICANCERIRBA IRSNCIRAD
FONDATION MERIEUX
ICGC Map
8
64 projects launched
CEA
CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRDARIIS EFS INERIS INSTITUT CURIE INSTITUT MINES-TELECOM UNICANCERIRBA IRSNCIRAD
FONDATION MERIEUX
ICGC: Liver Cancer genome programme
9
Guichard et al. Nature Genetics, 2012
CEA
CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRDARIIS EFS INERIS INSTITUT CURIE INSTITUT MINES-TELECOM UNICANCERIRBA IRSNCIRAD
FONDATION MERIEUX
Proof of concept for molecularly guided therapy: prospective trial for the future
10
Need to demonstrate that sequencing tumours (Exome-Whole GS) is of interest for treatment decision
A national cooperative randomized study in early metastatic patient in some tumour types
Comparing therapeutic decision based on NGS to current diagnostic procedures including defined genetic tests
To be performed in the CLIP2 (INCa- Fondation ARC- Unicancer)
With the help of Pharmas to provide drugs already in phase 2 trials
CEA
CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRDARIIS EFS INERIS INSTITUT CURIE INSTITUT MINES-TELECOM UNICANCERIRBA IRSNCIRAD
FONDATION MERIEUX
Conclusions and perspectivesThe French molecular screening initiative :
has been operational for 5 years for access to targeted therapies
Opens the path to switch to complete genomics and personalized
therapy
is an opportunity to improve patient accrual into clinical trials
Current research on genomics of cancer
is the basis to understand the steps of cancer development,
identify new targets and develop new therapies through the
synergy between fundamental, translational and clinical sciences
Allows to foster on innovation through bioinformatics, biomarkers
and drug development
11
CEA
CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRDARIIS EFS INERIS INSTITUT CURIE INSTITUT MINES-TELECOM UNICANCERIRBA IRSNCIRAD
FONDATION MERIEUX
12
CEA
CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRDARIIS EFS INERIS INSTITUT CURIE INSTITUT MINES-TELECOM UNICANCERIRBA IRSNCIRAD
FONDATION MERIEUX
Rapid access to innovation
13
Mid 2008 : EMA approvals for panitumumab and
cetuximab for patients with wild type KRAS
tumours
Allocation of €2.5M to the 28 centres at the end of
2008
June 2009 : gefitinib approvals by EMA for
patients with activating mutations of EGFR in
their tumors
Allocation of €1.7M to the 28 centres at the
end of 2009
Offer each patient in France an equal access to molecular tests as soon as a new targeted therapy is available
CEA
CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRDARIIS EFS INERIS INSTITUT CURIE INSTITUT MINES-TELECOM UNICANCERIRBA IRSNCIRAD
FONDATION MERIEUX
Surveys of mutation databases indicate that most mutations are found in many
tumour types
14
Sanger Institute: http://www.sanger.ac.uk/cosmic, COSMIC v54 Release (Forbes et al., 2011).
CEA
CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRDARIIS EFS INERIS INSTITUT CURIE INSTITUT MINES-TELECOM UNICANCERIRBA IRSNCIRAD
FONDATION MERIEUX
Targeted therapies with sufficient preclinical and clinical data (level 1)
15
Activation of AKT/mTor pathway (20%)
Private mutations (2%)
Activation of ras/raf/MAP kinase
pathway (9 %)
Cytokine and growth factor receptors (7%)
PIK3CA mutations (1%)TSC1 and TSC2 mutations (7%)
PTEN HD (2%)Activation without
known mutation (10%)
BRAF mutation (1%)
FGF19 amplification (1%)
EGFR overexpression (1%)
HER2neu overexpression (1%)
SUFU mutation (1 %)
MGMT HD (1%)
Targeted therapy
mTor inhibitor (everolimus, sirolimus)
BRAF V600 inhibitor (vemurafenib)
FGFR inhibitor(pazopanib)
Antibody anti-EGFR (cetuximab)
Antibody anti-HER2(trastuzumab)
Inhibitor of sonic hedgehog (vismodegib)
Oral alkylating agent (temozolomid)
Courtesy of Nault and Zucman, unpublished
CEA
CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRDARIIS EFS INERIS INSTITUT CURIE INSTITUT MINES-TELECOM UNICANCERIRBA IRSNCIRAD
FONDATION MERIEUX
Putative targeted therapies: on-going pre-clinical analyses (level 2)
16
Activation of NFE2L2/KEAP1 pathway
(20 %)
Activation of ras/raf/MAP kinase pathway (9 %)
Cytokine and growth factor receptors (7 %)
NFE2L2 mutation (5%)KEAP1 mutation (3%)
Activation without known mutation (12%)
RPS6KA3 mutation (8%)
IL6ST mutation (2%)
HSP90 inhibitor (17-AAG and 17-
DMAG)
MEK 1/2 inhibitor
(selumitinib)
JAK1/JAK2 inhibitor (ruxolitinib)
Courtesy of Nault and Zucman, unpublished
Targeted therapy
CEA
CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRDARIIS EFS INERIS INSTITUT CURIE INSTITUT MINES-TELECOM UNICANCERIRBA IRSNCIRAD
FONDATION MERIEUX
17
SAFIR02
Metastatic Her2-neg breast cancer
pretreated with 1 line chemotherapy
Metastatic EGFR / ALK wt lung cancer not pretreated with
chemotherapy
Biopsy Metastatic Site:NGS target gene
sequencing
Chemotherapy:
6-8 cycles
No alterationOr non druggable
Druggablemolecularalteration
Not included
R
Arm A: targeted therapyAccording to the
molecular alteration
Arm B: best available therapy
Based on available mono-test
PR, SD
PI: Fabrice AndréSponsor: UNICANCER- Funding partners INCa-ARC N: 1000 for screening, 400 for therapeutic phase
CEA
CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRDARIIS EFS INERIS INSTITUT CURIE INSTITUT MINES-TELECOM UNICANCERIRBA IRSNCIRAD
FONDATION MERIEUX
2012 2012 datadata
18
CEA
CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRDARIIS EFS INERIS INSTITUT CURIE INSTITUT MINES-TELECOM UNICANCERIRBA IRSNCIRAD
FONDATION MERIEUX
Liver Cancer genome programme
19
Guichard et al. Nature Genetics, 2012