Obesity, Inflammation and Liver Cancer

Transcription

1 Obesity, Inflammation and Liver Cancer Richard Moreau, M.D., 1 INSERM U773, Centre de Recherche Biomédicale Bichat-Beaujon CRB3, 2 Université Denis Diderot Paris 7, 3 Service d Hépatologie, Hôpital Beaujon, Clichy/Paris, France richard.moreau@inserm.fr 1

2 HUMANS Obesity Causes Non-Alcoholic Fatty Liver Disease (NAFLD) Spectrum of Hepatic Pathology Steato-hepatitis (NASH) Steatosis Cirrhosis Hepatocellular carcinoma

3 MICE Obesity Promotes Liver Inflammation and Cancer by Enhancing Pro-Inflammatory Cytokines Inflammation Cirrhosis

4 Human NAFLD: Where Are We? Genes associated with progression to cancer: Unknown Role of meta-genome: Unknown Biomarkers for different stages of NAFLD, including cancer: Unknown Intra-hepatic cytokine signaling associated with cancer: Unknown Current therapies: ineffective or poorly effective

5 Where Should We Go? Perform GWAS of cancer in NAFLD Investigate meta-genome Identify biomarkers for disease progression Investigate intra-hepatic cytokine signaling to identify targets for new molecules Evaluate new molecules in clinical trials

6 Where Should We Go? Perform GWAS of cancer in NAFLD Investigate meta-genome Identify biomarkers for disease progression Investigate intra-hepatic cytokine signaling to identify targets for new molecules Evaluate new molecules in clinical trials

7 Cohorts For GWAS, Metagenomics & Biomarkers Cohort of patients with NAFLD: - FLIP (Fatty Liver: Inhibition of Progression) - French PI; Sponsor: EU/FP7-HEALTH, - Recruiting ( ); size: 1,200 patients. The culture of cohort in France: - 4 Cohorts; cirrhotics (alcohol, HBV, HCV) - Sponsor: French Ministry of Health - 2,800 patients already enrolled.

8 Where Should We Go? Perform GWAS of cancer in NAFLD Investigate meta-genome Identify biomarkers for disease progression Investigate intra-hepatic cytokine signaling to identify targets for new molecules Evaluate new molecules in clinical trials

9 Identify Targets of New Molecules For NAFLD 38 French Academic Labs Dedicated to Liver Diseases: Aviesan Cannabinoids Affect Liver Inflammation and Fibrosis Sophie Lotersztajn and colleagues, Nat Med 2006

10 Identify Targets of New Molecules For NAFLD 38 French Academic Labs Dedicated to Liver Diseases: Aviesan gp130 Mutations in Inflammatory Hepatocellular Tumors IL-6 gp130 IL-6R Jessica Zucman-Rossi and colleagues, Nature 2009

11 Tumor Samples Are Already Available: French Collection of Liver Tumors BIOBANKS INSTITUTIONS USE 8 liver biobanks in France 1,200 samples: - partial or total hepatectomy - standardized clinical, biological and histological annotations. Inserm Institut National du Cancer University Hospitals : - AP-HP Paris: Beaujon, H. Mondor, A. Béclère, and P. Brousse hospitals - Bordeaux, Rennes, Toulouse, Grenoble International Cancer Genome Consortium: 500 paired non-tumor and tumor tissues

12 Where Should We Go? Perform GWAS of cancer in NAFLD Investigate metagenome Identify biomarkers for disease progression Investigate intra-hepatic cytokine signaling to identify target for new molecules Evaluate new molecules in clinical trials

13 Liver Units in French Academic Health Centers (AHCs) For Randomized Clinical Trials (RCTs) 27 Liver Units in AHCs, 22 with liver transplantation Expertise for management of liver diseases Routine liver biopsy Pathologists and radiologists dedicated to liver diseases Involvement in international consortia: - EUROIRON 1 (EU/FP6) - Chronic liver failure (CLIF) Consortium (European Association for the Study of the Liver) - European Network for Vascular Disorders of the Liver

14 The Anti-inflammatory Pentoxifylline For Patients With Advanced Cirrhosis Survival Without Complications Tenofovir vs. Adefovir For Chronic Hepatitis B Pentoxifylline (n=164) Placebo (n=171) P=0.03 Lebrec et al. Gastroenterology 2010 Telaprevir and Peginterferon With or Without Ribavirin For Chronic Hepatitis C Marcellin et al. N Engl J Med 2008 Hézode et al. N Engl J Med 2009

15 Conclusions In the next years, in the field of NAFLD, French research will contribute to: - Identify genetic and/or meta-genonomic factors associated with disease progression, - Identify biomarkers for different disease stages, - Identify targets for new molecules. French Liver Units are good candidates for performing RCTs of new molecules for NAFLD. 15