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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. Personalized medicine. Early diagnosis
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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
Personalized medicine • Early diagnosis • The right treatment for the right patient at the right time
Patient heterogeneity Tumor molecular heterogeneity RAS EGFR MYC MET
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
Control radio/echo Biopsies 18 gauges • SNAP FROZEN or RNA LATTER • HISTOLOGY CONTROL • Lesions of 2 cm • Avoid necrosis ( use functional imaging
SOP pain, anxiety and risk management Radiologie-Interventionnelle team (Dr T De BAERE)
ANOVA Repondeur /NRepondeur (4 5 8 / 1 3 7)poor quality of signature
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.
Metastasis and angiogenesis are linked
normal tumoral Tumors induces angiogenic signals to stimulate vessels growth angiogenesis Jain RK, Science, 2005
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
Patient 1 NSCLC metastating Progressing after anti EGFR treatment Angiogenic molecular profile Increased expreesion of VEGFA 4 fold Good candidate for Avastin
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.
2 Male Caucasian,58Y, 2003, NSCLC, cT4,N0,M1 • 9 therapeutic linesCisplatin-GemzarTaxotereNavelbineTaxol-CarboplatinMediastinal RadiotherapyIRESSAAlimtaTarcevaHKI 272 (included in clinical trial) (pan Her Inhibitor)
4 Baseline START HKI272 Adrenal node (C2) = 26 mm
Adrenal node (C2) = 58 Disease Progression New sublclavious metastasis 7 Progression Disease DECISION TO STOP HKI 272
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
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,
12 Cisplatin 63 Taxotere 80 Gemzar 70 IRESSA 80
16 01/07/09: -may 2010Still on Lapatinib, Xeloda,Thiotepa Stable Disease !! Increasing weight, good quality of life
17 Future weapons • Fotemustine (score 627) • Rituximab (score 761) • Trabectidin (score 376) • Vorinostat score >300
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.
11-01-10 Baseline 10-03-10 After 2 cycles
11-01-10 Baseline 10-03-10 After 2 cycles
11-01-10 Baseline 10-03-10 After 2 cycles
11-01-10 Baseline 10-03-10 After 2 cycles
WIN GAP • Worldwide Innovative Networking • Initiated By MDACC and IGR Only 50 % cured Late diagnosis Therapeutic failure
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
WORLDWIDE INNOVATIVE NETWORKING IN CANCER PERSONALIZED MEDICINE The WIN organization www.winconsortium.org
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
WIN President John Mendelsohn Chairman of steering commitee Vladimir Lazar Direction of stragy Hilario Mata Direction of operations Project managers
A special issues of Nature Reviews dedicated to WIN Launching the Journal of Personalized Medicine
Stanley Hamilton, Lajos Pusztai, Ignacio Wistuba Juri Gelovani 40