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Transcript of p53 isoforms: a major pronostic marker of the metastasis … · p53 isoforms: a major pronostic...
p53 isoforms: a major pronostic marker of the metastasis risk
Pierre Roux CRBM/ UMR5237 Montpellier, France
17 May 2016
Invasive modes
Invasion metastases
Primary tumor
Market needs
• Metastases: cause of cancer death
• Pronostic marker : prediction of relapse/metastases
• Therapeutic option: guided by the risk
• Europe: > 446 000 new cases/y colorectal cancer (CRC), > 463 000 /breast
• Biomarker in oncology: 15 Md $ in 2013 (35 Md $ in 2018)
• Urgent need of specific biomarkers of metastasis
A biomarker predicts the risk of recidive
Primary tumor
Biomarker: Personalized therapy
Weak risk: Chemotherapy reduced
High risk: Intensified chemotherapy
Stratification: Targeted theray
Increased survival rate
No biomarker: Colorectal cancer 70% overtreatment
No biomarker: Breast cancer
30% inadequate treatment
1 2 3 4
1 2 3 4 gene
protein
Alternative splicing pre mRNA
mRNA
Isoform A
1 2 3 1 2 3 4 1
Isoform B
Transcription
Alternative splicing generates modified proteins
Alternative splicing as an unexplored program in oncology
Major
3 4
p53: a key role in cancer
Isoforms : modified p53 p53
• The most tumor suppressor studied • The most frequent mutated gene in cancer • Inactivated function in almost all tumors
Robust biomarker of metastasis risk Unreliable biomarker
Mutated p53
331
p53γ p53β
Δ40p53
Δ40p53β Δ40p53γ
Δ133p53 Δ 133p53β Δ 133p53γ
p53
Alternative Splicing Mutation
A clinical biomarker to predict high risk of relapse in advanced breast cancer
Cum
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ive
Dis
ease
Fr
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Breast cancer: 273 tumors • 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
p53 isoforme: Δ133p53β
Low
High
Opportunity to position p53 isoforms test in breast cancer
Newly diagnosed early invasive breast cancer
Metastatic breast cancer or locally advanced High risk node negative
ER positive (Luminal A)
p53 isoforms test
HER2 positive Triple negative
• 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
A clinical biomarker to predict high risk of relapse in advanced rectal cancer
• 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
Rectal cancer
Cum
ulat
ive
Dis
ease
Fr
ee S
urvi
val
Low
High
p53 isoform: Δ133p53β
Biomarkers Oncotype DX/Mammaprint p53 isoform Signature Multiplex Monogenic Specificity Weak (63% Oncotype DX) High(93%) Mechanism Non-identifiable Identifiable Associated targeted therapy Impossible Potential Targeting Cost High
(4000 $ Oncotype DX) Reduced (estimated cost < 25 €)
Sample Paraffin (Oncotype DX) / Frozen (Mammaprint)
Paraffin and frozen
Competitive position
• Colorectal cancer: no test available
• Breast cancer
Positioning in the value chain developement
Identification Scientific Validation
Pre-Clinical optimization
Clinical trials
Research Clinic Development
Hit Lead
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
IP Status
• 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/30.06.09/EP09305 633.1. 2. Gadea G. Arsic N., Fort P. and Roux P. : Reprogramming method for producing Induced Pluripotent Stem Cells (iPSC). Patent EP/ 30.01.2015/EP15305145. 3. Arsic N., Gadea G., Fort P. and Roux P. : ∆133p53ß and ∆133p53γ are biomarkers of cancer stem cells, Patent EP/30.01.2015/EP15305146.
• 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)