p53 isoforms: a major pronostic marker of the metastasis risk

Transcription

1 p53 isoforms: a major pronostic marker of the metastasis risk Pierre Roux CRBM/ UMR5237 Montpellier, France Invasive modes 17 May 2016 Primary tumor Invasion metastases

2 Market needs Metastases: cause of cancer death Pronostic marker : prediction of relapse/metastases Therapeutic option: guided by the risk Europe: > new cases/y colorectal cancer (CRC), > /breast Biomarker in oncology: 15 Md $ in 2013 (35 Md $ in 2018) Urgent need of specific biomarkers of metastasis

3 A biomarker predicts the risk of recidive Primary tumor Biomarker: Personalized therapy Weak risk: Chemotherapy reduced No biomarker: Colorectal cancer 70% overtreatment High risk: Intensified chemotherapy No biomarker: Breast cancer 30% inadequate treatment Stratification: Targeted theray Increased survival rate

4 Alternative splicing generates modified proteins gene Transcription pre mrna Alternative splicing mrna protein Major Isoform A Isoform B Alternative splicing as an unexplored program in oncology

5 p53: a key role in cancer The most tumor suppressor studied The most frequent mutated gene in cancer Inactivated function in almost all tumors Mutated p53 Mutation p53 Alternative Splicing p53 Isoforms : modified p53 p53β p53γ Δ40p53 Δ40p53β Δ40p53γ Δ133p53 Δ 133p53β Δ 133p53γ Unreliable biomarker Robust biomarker of metastasis risk

6 A clinical biomarker to predict high risk of relapse in advanced breast cancer p53 isoform test: Associated with reduced disease free survival (DFS) and global survival, independently of p53 mutations Predicts high risk of relapse High specificity (93%) Help guide treatment decision-making in selecting which patients should benefit from additional therapy Breast cancer: 273 tumors Cumulative Disease Free Survival p53 isoforme: Δ133p53β Low High

7 Opportunity to position p53 isoforms test in breast cancer Newly diagnosed early invasive breast cancer High risk node negative Metastatic breast cancer or locally advanced ER positive (Luminal A) HER2 positive Triple negative p53 isoforms test Needs: Luminal A : hormone sensitive cancer (70% of breast tumors) 30 % (undetectable) of relapse/metastases in 4 years Predict risk of relapse or treatment failure in Luminal A Adapt treatment strategy

8 A clinical biomarker to predict high risk of relapse in advanced rectal cancer Rectal cancer p53 isoform: Δ133p53β Needs: Single chemotherpy treatment 70 % overtreatment Adapt treatment strategy p53 isoform test: Associated with reduced disease free survival (DFS) and global survival, independently of p53 mutations Predict high risk of relapse High specificity (95%) Help guide treatment decision-making in selecting which patients should benefit from additional therapy All patients may benefit from this test Cumulative Disease Free Survival Low High

9 Competitive position Colorectal cancer: no test available Breast cancer Biomarkers Oncotype DX/Mammaprint p53 isoform Signature Multiplex Monogenic Specificity Weak (63% Oncotype DX) High(93%) Mechanism Non-identifiable Identifiable Associated targeted therapy Impossible Cost High (4000 $ Oncotype DX) Sample Paraffin (Oncotype DX) / Frozen (Mammaprint) Potential Targeting Reduced (estimated cost < 25 ) Paraffin and frozen

10 Positioning in the value chain developement Identification Hit Scientific Validation Lead Pre-Clinical optimization Clinical trials Research Development Clinic p53 isoform Reliable and robust method (qpcr) High sentitivity and specificity Original mechanism Highly relevant target Meets a market need Needs of ressources Optimization detection kit Design of clinical trials Partnership/ Investors

11 IP Status Scope of patents protection: 1. Method of detection (prediction) 2. Method to assess cancer aggressiveness (pronostic) 3. Method to determine resistance to therapy (chemoresistance) 4. Method to screen anti-metastasic compounds (theranostic) Patents : 1. Bourdon J-C, Fernandez K., Gadea G., Anguille C., Vinot S., and Roux P. Method for testing a subject thought to be predisposed to having cancer : 133p53b : a biomarker of metastatic cancer. Patent EP/ /EP Gadea G. Arsic N., Fort P. and Roux P. : Reprogramming method for producing Induced Pluripotent Stem Cells (ipsc). Patent EP/ /EP Arsic N., Gadea G., Fort P. and Roux P. : 133p53ß and 133p53γ are biomarkers of cancer stem cells, Patent EP/ / EP

12 Pierre Roux Véronique Gire Nikola Arsic Peggy Raynaud Philippe Fort Emmanuel Vignal Fanny Tomas Samer Abdallah Anne-Sophie Dume Team: Dynamic of cancer invasion CRBM Institute, CNRS, Montpellier, France