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ITMO Cancer

ITMO Cancer. From Precision to Personalised Medicine Brussels 24/09/2013. CEA. CHRU. CNRS. CPU. INRA. INRIA. INSERM. INSTITUT PASTEUR. IRD. ARIIS. CIRAD. EFS. FONDATION MERIEUX. INERIS. INSTITUT CURIE. INSTITUT MINES-TELECOM. IRBA. IRSN. UNICANCER.

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ITMO Cancer

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  1. ITMO Cancer From Precision to Personalised Medicine Brussels24/09/2013 CEA CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRD ARIIS CIRAD EFS FONDATION MERIEUX INERIS INSTITUT CURIE INSTITUT MINES-TELECOM IRBA IRSN UNICANCER

  2. 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

  3. How are we currently using genomics in patient management?

  4. Structures and Infrastructures: Molecular genetic centers • High quality molecular testing, all patients, anywhere in France • PartnershipsbetweenUniversityhospitals and cancer centers • Regionalorganization • PPPswith Roche, Amgen, Pfizer, GSK, AZ

  5. From genetic centers to biology driven therapy F Nowak, JC Soria and F Calvo, Nat Rev Clin Oncol. 2012

  6. An increasing number of actionable molecular alterations • 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

  7. Single genes Gene panels Exomes Whole genomes • Gene expression profiles • Copy Number Variation 2000 2010 2015 • New technologies… have resulted in > 100,000-fold decreases in sequencing costs: • $1,000/genome will soon be achieved

  8. ICGC Map 64 projects launched

  9. ICGC: Liver Cancer genome programme Guichard et al. Nature Genetics, 2012

  10. Proof of concept for molecularly guided therapy: prospective trial for the future • 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

  11. Conclusionsand perspectives The 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

  12. Rapid access to innovation Offer each patient in France an equal access to molecular tests as soon as a new targeted therapy is available 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

  13. Surveys of mutation databases indicate that most mutations are found in many tumour types Sanger Institute: http://www.sanger.ac.uk/cosmic, COSMIC v54 Release (Forbes et al., 2011).

  14. Targeted therapies with sufficient preclinical and clinical data (level 1) Targetedtherapy PIK3CA mutations (1%) TSC1 and TSC2 mutations (7%) PTEN HD (2%) Activation without known mutation (10%) Activation of AKT/mTor pathway (20%) mTor inhibitor(everolimus, sirolimus) Activation of ras/raf/MAP kinase pathway (9 %) BRAF V600 inhibitor (vemurafenib) BRAF mutation (1%) FGFR inhibitor (pazopanib) FGF19 amplification (1%) EGFR overexpression (1%) HER2neu overexpression(1%) Cytokine and growth factor receptors (7%) Antibody anti-EGFR (cetuximab) Antibody anti-HER2 (trastuzumab) SUFU mutation (1 %) MGMT HD (1%) Inhibitor of sonic hedgehog(vismodegib) Private mutations (2%) Oral alkylating agent (temozolomid) Courtesy of Nault and Zucman, unpublished

  15. Putative targeted therapies: on-going pre-clinical analyses (level 2) Targetedtherapy NFE2L2 mutation (5%) KEAP1 mutation (3%) Activation without known mutation (12%) HSP90 inhibitor (17-AAG and 17-DMAG) Activation of NFE2L2/KEAP1 pathway (20 %) MEK 1/2 inhibitor (selumitinib) Activation of ras/raf/MAP kinase pathway (9 %) RPS6KA3 mutation (8%) JAK1/JAK2 inhibitor (ruxolitinib) Cytokine and growth factor receptors (7 %) IL6ST mutation (2%) Courtesy of Nault and Zucman, unpublished

  16. SAFIR02 BiopsyMetastatic Site: NGS targetgenesequencing Arm A: targeted therapy According to the molecular alteration R Druggable molecular alteration Arm B: best availabletherapy Based on available mono-test Metastatic Her2-neg breast cancer pretreatedwith 1 line chemotherapy Metastatic EGFR / ALK wtlung cancer not pretreatedwithchemotherapy Chemotherapy: 6-8 cycles PR, SD PI: Fabrice André Sponsor: UNICANCER- Fundingpartners INCa-ARC N: 1000 for screening, 400 for therapeutic phase No alteration Or non druggable Not included

  17. 2012 data 36,4% 3,9%

  18. Liver Cancer genome programme Guichard et al. Nature Genetics, 2012

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