6th CCO, Shanghai, May 21th 2010

1. Technology and Methodology needed to personalized medicine for cancer treatments: realities and challenges Vladimir Lazar, MD, PhD Director of Genomic Research Centre Institut Gustaver Roussy, France 6th CCO, Shanghai, May 21th 2010

2. Personalized medicine • Early diagnosis • The right treatment for the right patient at the right time

3. Patient heterogeneity Tumor molecular heterogeneity RAS EGFR MYC MET

6. Technologies and methodologies needed • Biopsies of good quality and histology relevance • Paired biopsies from Tumoral and Normal tissue • Use of appropriate technologies • Functional genomics Gene expression and miRNA • Mutations (EGFR, KIT, RAS, BRAF, PTEN, PI3K etc • Comparative genomic hybridization ( CGH) • New algorythms to predict efficacy of drugs • Validation and international cooperation

7. Control radio/echo Biopsies 18 gauges • SNAP FROZEN or RNA LATTER • HISTOLOGY CONTROL • Lesions of 2 cm • Avoid necrosis ( use functional imaging

8. SOP pain, anxiety and risk management Radiologie-Interventionnelle team (Dr T De BAERE)

9. ANOVA Repondeur /NRepondeur (4 5 8 / 1 3 7)poor quality of signature

10. High accuracy of molecular signature

11. Aberrations detected in cancers are related to: • Control of cell cycel • DNA reparation • Apoptosis • Senescence • Angiogenesis • Invasion The hallmarks of cancer Cell 2000; 100: 57-70.

12. Metastasis and angiogenesis are linked

13. normal tumoral Tumors induces angiogenic signals to stimulate vessels growth angiogenesis Jain RK, Science, 2005

14. Activators and et inhibitors of angiogenesis Inhibitors: Degradation of MEC: TIMPs Control of proliferation : Angiostatine, Endostatine, Migration : Canstatine, Thrombospondine Cytokine anti angiogenesis : IL-12, TNF, IFN Activatiors: Growth factors :VEGF, Angiopoïetines, bFGF, PDGF, TGF, HGF, Protases : MMPs, uPA, tPA. Adhesibo : Intégrines Cytokines pro-angiogenesis : IL-8, tumoral angionenic switch D’après G Bergers et al, 2003

15. An example of personalized choice of drugs

16. Patient 1 NSCLC metastating Progressing after anti EGFR treatment Angiogenic molecular profile Increased expreesion of VEGFA 4 fold Good candidate for Avastin

17. Patient 2 NSCLC indifferentiated progressing under carboplatin and vincristine Angiogenic profile Avastin bad choice because is not targeting VEGFC, Only possible choices sorafenib ou sunitinib.

18. 2 Male Caucasian,58Y, 2003, NSCLC, cT4,N0,M1 • 9 therapeutic linesCisplatin-GemzarTaxotereNavelbineTaxol-CarboplatinMediastinal RadiotherapyIRESSAAlimtaTarcevaHKI 272 (included in clinical trial) (pan Her Inhibitor)

19. 4 Baseline START HKI272 Adrenal node (C2) = 26 mm

20. Adrenal node (C2) = 58 Disease Progression New sublclavious metastasis 7 Progression Disease DECISION TO STOP HKI 272

21. Building of algorithme relies on 3 steps 9 Complet genome profiling of the Tumor (metastasis) as compared to the original histological normal tissue Tumor Normal Cancer is a clonal disease Cancer is a polygenic disease Drivers are mutations

22. 10 Second step Identifiction of all genes altered by The drugs, or interacting with drugs Understanding of the interaction drug-gene ( genes of resistance, targets, genes of sensitisation,

23. 12 Cisplatin 63 Taxotere 80 Gemzar 70 IRESSA 80

24. 16 01/07/09: -may 2010Still on Lapatinib, Xeloda,Thiotepa Stable Disease !! Increasing weight, good quality of life

25. 17 Future weapons • Fotemustine (score 627) • Rituximab (score 761) • Trabectidin (score 376) • Vorinostat score >300

26. NSCLC, stage IV • 63 yrs old • Adenocarcinoma, lung metastasis • Gemcitabine, cisplatine, 13 cycles : partial response then progression • Alimta, 4 cycles : progression • bevacizumab began on Jan 22th.

27. 11-01-10 Baseline 10-03-10 After 2 cycles

28. 11-01-10 Baseline 10-03-10 After 2 cycles

29. 11-01-10 Baseline 10-03-10 After 2 cycles

30. 11-01-10 Baseline 10-03-10 After 2 cycles

31. WIN GAP • Worldwide Innovative Networking • Initiated By MDACC and IGR Only 50 % cured Late diagnosis Therapeutic failure

32. WIN GOALS • Early Diagnosis • Individualized Treatments • Harmonization and standardisation Focus • Validation of new tools, concepts, technologies • Generation of standardized industrial kits • An operational structure; The WIN consortium • Dissemination of knowledge: The WIN symposium Strategy First concrete results in 3-5 years Critic mass in relationship with Pharma and Regulatories Generate incoming revenues Expected results Accelerate integration of ground-breaking personalized cancer medicine discoveries into clinical practice and to significantly improve clinical outcome and quality of life

33. WORLDWIDE INNOVATIVE NETWORKING IN CANCER PERSONALIZED MEDICINE The WIN organization www.winconsortium.org

34. WIN WIN concept • Innovation corresponding to a clearly identified medical need • The application can be developed as a point of care solution • The method, technology or concept is protected or can be protected by a patent (granted or filed) and can be developed as a commercial product. • Evaluation by independent Scientifi Advisory Board • Ranking and proposal for 3-5 projects/ anum • The vote of the steering committee ( quorum 80% and majority of 75%- during the annual general assembly • Ressource allocation and fund raising. Eligibility Decision • Each founder preserve freedom to operate, entire control and entire Control of IP • Each Founder propose validation project dedicated to Early Diagnosis ane Individualized Treatments

35. WIN President John Mendelsohn Chairman of steering commitee Vladimir Lazar Direction of stragy Hilario Mata Direction of operations Project managers

37. A special issues of Nature Reviews dedicated to WIN Launching the Journal of Personalized Medicine

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40. Stanley Hamilton, Lajos Pusztai, Ignacio Wistuba Juri Gelovani 40