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Session 2.1: Kinkhabwala
- 1. UNIFYING STRATEGIES FOR THERAPEUTIC INTERVENTION IN HEPATOCELLULAR CARCINOMA Professor of Surgery Montefiore Einstein Liver Center MILAN KINKHABWALA, MD
- 7. Hepatology. 2008 October; 48(4): 1312–1327.
- 9. Hepatology. 2008 October; 48(4): 1312–1327 .
- 20. FUNCTION Gene Gene Expression Mutations/Copy alterations Aberrant methylation Growth factors and receptors IGF-II Increased IGFR-II (M6PR) Decreased 25%/LOH 60% EGF Increased EGFR Increased 0% TGF-alpha Increased K-RAS - 11% (3-42%) RASSF1 Decreased 85% PIK3CA - 12% (0-35%) PTEN Decreased 0-11% HGF/c-MET Increased Proliferation and differentiation β-catenin Increased 17% (0-44%); 58%,hepatoblastoma E-cadherin Decreased Hyper: 46% c-myc Increased Hypo APC Decreased 77% Angiogenesis VEGFA Increased Amplification (5%) VEGFR-2 Increased Angiopoietin-2 Increased Metastasis MMP-14 Increased MMP-9 Increased Topoisomerase 2A Increased Osteopontin Increased Cell cycle Rb Increased 15% cyclin D1 Decreased Amplification (7%) p53 Decreased 27% (0-67%) p16 Decreased 13% Hyper: 56% p27kip Decreased Survivin Increased
- 21. Llovet and Bruix, Hepatology, 2008
- 22. Molecular targeted therapy for HCC Drug Type of Drugs Molecular Targets Affected Signaling Pathways FDA Approval Sorafenib Tyrosine kinase inhibitor VEGFR, PDGFR, RAF VEGFR, PDGFR, RAS/MAPK yes Sunitinib Tyrosine kinase inhibitor VEGFR, PDGFR, c-kit VEGFR, PDGFR, c-kit No, phase II or 3 trials Bevacizumab Monoclonal antibodies to ligand VEGFR VEGFR No, phase II or 3 trials Cetuximab Monoclonal antibodies to ligand EGFR EGFR No, phase II or 3 trials Erlotinib Tyrosine kinase inhibitor EGFR EGFR No, phase II or 3 trials Gefitinib Tyrosine kinase inhibitor EGFR EGFR No, phase II or 3 trials Lapatinib Tyrosine kinase inhibitor Her-2/neu Her-2/neu No, phase II or 3 trials Rapamycin ST kinase inhibitor mTOR PIK3/Akt/mTOR No, phase II or 3 trials Everolimus ST kinase inhibitor mTOR PIK3/Akt/mTOR No, phase II or 3 trials XL-765 ST kinase inhibitor PI3K PIK3/Akt/mTOR No, phase II or 3 trials Trastuzumab monoclonal antibodies to receptor Her-2/neu Her-2/neu No, phase II or 3 trials
- 23. Gene Expression in HCC: Differential gene expression in nontumoral tissue predicts outcome : Opportunity for individualizing therapeutic intervention? Survival Signatures and Survival Curves in the Training Set Hoshida Y et al. N Engl J Med 2008;359:1995-2004
Editor's Notes
- Figure 2. Survival Signatures and Survival Curves in the Training Set. Curves are shown for survival according to the association of the gene signature with survival, based on leave-one-out cross-validation testing (Panel A), and for overall survival according to the level of expression of the 186 signature genes (Panel B); of these, 113 were associated with a good prognosis and 73 with a poor prognosis. Panel C shows the expression pattern of the survival signature (comprising 186 genes). The 20 genes most closely associated with a poor prognosis are listed on the left, and the 20 most closely associated with a good prognosis on the right. Red indicates high expression; blue indicates low expression. Panel D shows representative photomicrographs of sections of liver tissue adjacent to tumor that were profiled in this study; there were no histologic correlates with survival. Staining was with hematoxylin and eosin.