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Session 2.1: Kinkhabwala
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Session 2.1: Kinkhabwala

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Milan Kinkhabwala

Milan Kinkhabwala

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  • 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.

Session 2.1: Kinkhabwala Session 2.1: Kinkhabwala Presentation Transcript

  • UNIFYING STRATEGIES FOR THERAPEUTIC INTERVENTION IN HEPATOCELLULAR CARCINOMA MILAN KINKHABWALA, MD Professor of Surgery Montefiore Einstein Liver Center
  • Goals in Liver Cancer • Using tumor biology to individualize intervention for HCC • Development of multimodality treatment algorithms incorporating development of molecular targets • Development of novel locoregional therapy
  • Design of an Integrated Care System for Liver Disease: Montefiore Einstein Liver Center • Division of Transplantation/Hepatobiliary Surgery • Division of Hepatology • Marion Bessin Liver Research Center
  • Montefiore Einstein Liver Center • Common inpatient and outpatient care system for medicine and surgery • Shared resources • Protocolized care • Common educational, clinical, and administrative meetings • Integration of basic science and clinical faculty
  • Hepatobiliary cancer working group • MELC core divisions • Division of Oncology • Department of Radiation Oncology • Division of Interventional Radiology Daily News
  • EPIDEMIOLOGY OF HCC • Worldwide 6th most common malignancy and 3rd leading cause of cancer deaths • HCC deaths are increasing the U.S., as a complication of HCV infection
  • Hepatology. 2008 October; 48(4): 1312–1327.
  • BIOPSY IS GENERALLY NOT VALUABLE IN HCC DIAGNOSIS • 137 PATIENTS UNDERGOING BIOPSY FOR SUSPECTED HCC (DURAND ET AL, J HEPATOLOGY 2001) • 122 + BIOPSIES/SENSITIVITY OF BIOPSY 90% • 13/15 PATIENTS WITH NEGATIVE BIOPSIES HAD HCC NEGATIVE BIOPSY HAS LOW PREDICTIVE VALUE WHEN INDEX OF SUSPICION IS HIGH BIOPSY MAY NOT CHANGE MANAGEMENT OR OUTCOME AND RISKS ARE HIGHER NEEDLE TRACK SEEDING 2-10%
  • Hepatology. 2008 October; 48(4): 1312–1327.
  • OPTIONS FOR THERAPEUTIC INTERVENTION Potentially Curative RESECTION TRANSPLANTATION ABLATION Noncurative but prolong survival TRANSCATHETER EMBOLIZATION SYSTEMIC THERAPY Efficacy and role still to be determined RADIOSURGERY
  • RESULTS AFTER RESECTION FOR SMALL HCC : GOOD EARLY LOCOREGIONAL CONTROL BUT LATE RECURRENCE RATES > 50% • MD ANDERSON, (Wayne et al, Annals of Surgery 2002). N=249 Estimated survival 41% and 19% at 5 and 8 years • PARIS VII UNIVERSITY (Belghiti, et al, Hepatogastroenterology 2002) N=328 37% 5 year survival • HONG KONG (NG, et al, Cancer 1995) N-278 Overall 17% 5 year disease free survival (34% overall) after resection
  • Validation of Liver Transplantation (total hepatectomy) as a Therapeutic Modality for HCC • 4 year disease free survival of 92% can be achieved for small unresectable HCC’s if specific imaging based tumor criteria are met. • Disease free survival was 59% if tumor exceed criteria. Mazaferro et al, 1996
  • Limitations of Transplantation • STILL 30% RISK OF RECURRENCE EVEN WITHIN T2 CRITERIA
  • LIMITATIONS OF TRANSPLANTATION • RECURRENT HCV RESULTS IN STAGE 4 FIBROSIS IN 30-50% BY YEAR 5 POST TRANSPLANT • ACCESS TO ORGANS/WAITING TIME RELATED DISEASE PROGRESSION (REQUIRES PRETRANSPLANT LOCOREGIONAL CONTROL) .25 .2 Cum. Hazar d .15 .1 Cumulative hazard of tumor .05 progression beyond acceptable UNOS criteria after listing for OLT 0 COLUMBIA PRESBYTERIAN MEDICAL CENTER 1997-2003 0 200 400 600 800 1000 Time
  • • Is it better to resect or transplant patients with HCV and early HCC?
  • Models of Hepatic Oncogenesis I. Adenoma II. Chronic inflammation Type 1: HNF1a mutation Chronic viral hepatitis HBV Type 2: HCV Wnt/bCatenin activation Inherited metabolic disorders Wilsons Hemachromatosis Type 3: Noninherited metabolic disorders No HNF or bCatenin mutations NAFLD III. Toxin/environmental carcinogens Aflatoxin B1
  • Pathogenesis of HCC • Heterogenous group of carcinomas with diverse molecular alterations • Continuous inflammation and regeneration of hepatocytes • Multistep accumulation of genetic/chromosomal alterations over years-decades – Hyperplastic change/macrogenerative nodules – Low grade to High grade Dysplasia – Early HCC – Advanced HCC • Upregulation of growth factors, inactivation of tumor suppressor genes, microsatellite instability
  • Hepatitis B Virus: direct and indirect oncogenic effects – Viral DNA integration into the genome causing disruption of chromosomal stability or tumor suppressor genes and/or activation of protooncogenes – Direct oncogenic effect of viral protein HBx (16.5kDa) which may regulate a number of viral and cellular genes: • Basal transcription machinery (TFIIB, TBP, RPB5) • Src pathway • Ras/Raf signaling • Amplification of TGFb – Indirect effects mediated by cellular immune responses
  • HCV • Mostly indirect effects (HCV viral DNA is never integrated into the genome) • Viral proteins (core protein in particular) may interfere with intracellular signalling resulting in inhibition of apoptosis
  • 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
  • Llovet and Bruix, Hepatology, 2008
  • 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
  • Survival Signatures and Survival Curves in the Training Set Gene Expression in HCC: Differential gene expression in nontumoral tissue predicts outcome: Opportunity for individualizing therapeutic intervention? Hoshida Y et al. N Engl J Med 2008;359:1995-2004
  • Kaplan–Meier curves showing the correlation between mTOR dysregulation and recurrence post resection for HCC Villanueva et al, Gastroenterology 2008
  • Can we use proteomics to discover a serum marker for early stage (curable) or occult HCC? • IRB approval obtained: – Blood from 10 patients with HCV cirrhosis with no HCC – Blood from 10 patients with HCV cirrhosis and known HCC – If surgery is performed, blood also collected from the hepatic vein effluent • Perform proteomic analysis Wolkoff, Angeletti, Kinkhabwala
  • MELC Projects Active tissue capture protocol Gaglio Prospective data collection using OTTR Kinkhabwala Clinical trials: Sorafenib v. Sunitinib Kaubisch Hepatitis C / Vertex Reinus RAD-001 (Phase II) Kaubisch Outcomes research in Hepatitis C Reinus Downstaging of HCC: Radiosurgery (Pilot) Gabeau Proteomic profiling of HCC Wolkoff/Kinkhabwala/Angeletti Biology of Liver Radiation Guha