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GCIG Meeting 29th May 2009 - PowerPoint PPT Presentation

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GCIG Meeting 29th May 2009
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  1. GCIG Meeting 29th May 2009 Ovarian Cancer Biology: Implications for Novel Targets and Strategic Pathways Iain McNeish Professor of Gynaecological Oncology Barts and the London School of Medicine LONDON

  2. Key targets in ovarian cancer High grade serous: p53 and BRCA/HR Endometrioid:  catenin, PI3K/PTEN Low grade serous: K-RAS, BRAF Mucinous: K-RAS All: Peritoneal microenvironment

  3. Key targets in ovarian cancer High grade serous: p53 and BRCA/HR Endometrioid:  catenin, PI3K/PTEN Low grade serous: K-RAS, BRAF Mucinous: K-RAS All: Peritoneal microenvironment

  4. BER/SSBR PARP ATM/R XRCC1 Pol Lig III FA core complex FANC D2 DNAreplication gH2AX BRCA1 Rad 51 Rad50 MRE11 DNA DSB NBS1 Rad 52/4 RPA ERCC1 XRCC3 BRCA2 HR repair Homologous recombination DNA SSB

  5. BER/SSBR PARP ATM/R XRCC1 Pol Lig III FA core complex FANC D2 DNAreplication gH2AX BRCA1 Rad 51 Rad50 MRE11 DNA DSB NBS1 Rad 52/4 RPA ERCC1 XRCC3 BRCA2 HR repair Synthetic lethality X DNA SSB X X X

  6. BRCA2-deficient cells and PARP inhibition Bryant et al Nature (2005) 434: 913

  7. BER/SSBR PARP DNA SSB ATM/R XRCC1 Pol Lig III FA core complex FANC D2 DNAreplication gH2AX BRCA1 Rad 51 Rad50 MRE11 DNA DSB NBS1 Rad 52/4 RPA ERCC1 XRCC3 BRCA2 HR repair • Combine with platinum*? * Cancer Res (2009) 69: 3850 Clin. Cancer Res. (2008) 14: 3916 PNAS (2008) 105: 17079 How to target sporadic ovarian cancer? • HR defective in 40% HGS • Multiple abnormalities • Treat all high grade serous? • Ex vivo assay for HR ‘competence’?

  8. Endometrioid 20% activating mutations p110 25% amplifications p110* 40% LOH 20% inactivating mutations 12% AKT2 amplification Platinum resistance PI3-kinase/AKT/PTEN • * Cancer Res. (2004) 64: 7678 • Cancer Res. (1998) 58:2095  Int J. Cancer (1995) 64: 280  n > 100

  9. PX-866 PI-103 PBI-05204 Perifosine Sirolimus Temsirolimus (CCI-779) Everolimus (RAD001) Deforolimus (MK-8669) PI3-kinase/AKT/PTEN

  10. 48 hours 1 week 2 weeks 3 weeks 4 weeks 8 weeks Tumour microenvironment Lectin CD45 GFP Andrew Leinster, Fran Balkwill

  11. Tumour microenvironment NEJM (2003) 348: 203 Nature Med (2004) 10: 942 PNAS (2005) 102:18538

  12. Targeting the microenvironment Potential targets TNF- IL-6 CCL2 Balkwill F. Nat. Rev. Cancer (2009) 9: 361