Subproject 4: Specification and Documentation of Metabolic and Neoplastic Diseases

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1 Subproject 4: Specification and Documentation of Metabolic and Neoplastic Diseases M. Trauner, Division of Gastroenterology and Hepatology, Department of Internal Medicine, MUG Co- Investigator: H. Samonigg, Division of Oncology, Department of Internal Medicine, MUG

2 Project aims Associate prospectively collected human tissue and blood samples with detailed patient information - Clinical presentation, disease course & outcome - Family history, life style, additional diseases, medication Cross-validate mouse models and corresponding human diseases - Metabolic liver diseases and liver cancer

3 Metabolic and neoplastic diseases Metabolism (obesity, diabetes, iron) & cancer - Liver, breast, colorectal, Chronic inflammatory liver / bowel disease cancer (end of a spectrum) - Fatty liver steatohepatitis cirrhosis HCC - Chronic hepatitis cirrhosis HCC - Ulcerative colitis dysplasia / DALM - CRC Underlying liver / GI disease + cancer

4 NAFLD: Spectrum of Hepatic Pathology Chronic metabolic liver disease leading to cancer Steatosis Steatohepatitis HCC Cirrhosis HCC Modified after: A. M. Diehl, AGA Slide Series

5 Prospective collection & annotation of patient samples Prospective collection of medical data and sera of patients undergoing liver and intestinal biopsies Serum samples from liver outpatients before, during and after therapy (including LTx) Serum samples from cancer outpatients before, during and after medical / surgical therapy

6 Lifestyle and family questionnaire Liver and oncology outpatient clinic Number of pages: 16, option for automatic scanning Time effort: 30 min for patients and 10 min for M.D. Patient acceptance: very high (99%) Personal and medical history: - Nutrition (3 pages) - Alcohol / nicotine consumption (2 p) - Physical activity (3 p, collaboration with Institute of Sports Medicine) - Past medical history (2 p) - Family history (5 p) - Medication (1 p) Number of life style questionnaires - Liver outpatient clinic: Oncology outpatient clinic: 741

7 Achieved project aims Prospective collection of serum und tissue samples consistent SOPs Centralized sample management Actual number of tissue samples: liver biopsies (23 chronic viral hepatitis, 11 fatty liver, 12 steatohepatitis, 11 cholestatic liver disease, 7 autoimmune hepatitis, 23 other etiology) intestinal biopsies (31 Crohn s disease, 19 ulcerative colitis, 9 normal controls, 77 other etiology) Actual number of serum samples: non-neoplastic liver diseases (viral, cholestatic, metabolic) - 35 hepatocellular carcinomas non-hepatic cancers (3.488 colon, rectal, breast) Merging of clinical und molecular data

8 Project aims Associate prospectively collected human tissue and blood samples with detailed patient information Cross-validate mouse models and corresponding human diseases - Metabolic liver diseases and liver cancer

9 Cross-validation of mouse models for metabolic liver diseases & liver cancer Cholesterol Mdr2 -/- mice BD BD Bile acids BD Bsep X X Abcg5/8 X Mdr2 PL MDR3 Mutations -PFIC3 (progressive familial intrahepatic cholestasis) -Sclerosing cholangitis -Intrahepatic cholestasis of pregnancy -Intrahepatic cholelithiasis -Drug induced cholestasis -Adult biliary cirrhosis Cftr Cl - Fickert et al, Gastroenterology, 2002 Lammert et al., Hepatology, 2004 Pikarsky et al., Nature 2004 Toxic bile Trauner et al, Wien Med Wochenschr, 2008 Ziol et al., Gastroenterology, 2008 AE2 induced bile duct injury HCO 3 - Cl -

10 Interdisciplinary experimental projects Morphological Characterization of Hepatic Carcinogenesis in the Mdr2-/- Mouse Model Department of Internal Medicine Division of Gastroenterology and Hepatology, Medical University of Graz Departement of Pathology, Medical University Graz Chromosomal instability in tumor development in Mdr2-/- mice Department of Internal Medicine Division of Gastroenterology and Hepatology, Medical University of Graz Departement of Medical Biology and Genetics, Medical University Graz Effects of 24-nor-UDCA in a hepatocellular carcinoma xenograft nude mouse model Department of Internal Medicine Division of Gastroenterology and Hepatology, Medical University of Graz Departement of Pathology, Medical University Graz

11 Publications funded by GATiB project (1/4) Side-chain-modification critically determines the physiologic and therapeutic properties of 24-norUrsodeoxycholic Acid in the treatment of sclerosing cholangitis in Mdr2 (Abcb4) Knockout Mice Emina Halilbasic 1, Peter Fickert 1, Romina Fiorotto 2, Hanns-Ulrich Marschall 3, Tarek Moustafa 1, Andrea Fuchsbichler 4, Judith Gumhold 1, Dagmar Silbert 1, Kurt Zatloukal 4, Cord Langner 4, Uday Maitra 5, Helmut Denk4, Mario Strazzabosco 2, and Michael Trauner 1 1 Laboratory of Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Medicine, Medical University Graz, Austria; 2 Section of Digestive Diseases, Department of Internal Medicine, School of Medicine, Yale University, New Haven, USA; 3 Karolinska University Hospital Huddinge, Stockholm, Sweden; 4 Institute of Pathology, Medical University Graz, Austria; 5 Departement of Organic Chemistry, Indian Institute of Science, Bangalore, India Hepatology 2009;49(6):

12 norudca as novel treatment for chronic liver injury and biliary fibrosis in Mdr2 -/- mouse model norudca T-norUDCA bis-nor norudca PL x Mdr2 -/- Anti-infammatory Anti-fibrotic Anti-proliferative Cholehepatic Shunting HCO 3 - Differences in HCO 3 - -rich Hypercholeresis Halilbasic et al., Hepatology, 2009

13 Cross-validation of mouse models for metabolic liver diseases & liver cancer Cholesterol Bile acids X FXR Bsep Abcg5/8 X Mdr2 PL WT Mdr2 -/- Mdr2/FXR DKO Cftr Cl - AE2 HCO 3 - Cl - Toxic bile induced bile duct injury

14 Summary Prospective collection of human tissue and blood samples with detailed clinical data from patients with metabolic and neoplastic disorders Cross-validation of corresponding mouse models

15 Thank you for your attention!