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Of mice and men – Development of a mouse model for intrahepatic cholangiocarcinoma Targeting BAP1 mutations in intrahepatic cholangiocarcinoma The Cholangiocarcinoma Foundation March 30, 2016 Overview Background • Intrahepatic cholangiocarcinoma and BAP1 • How we study cancer • Mouse models • The KPC mouse An example ICC and BAP1 • Existing ICC models • BAP1 GEMM development Overview Background • Intrahepatic cholangiocarcinoma and BAP1 • How we study cancer • Mouse models • The KPC mouse An example ICC and BAP1 • Existing ICC models • BAP1 GEMM development Cholangiocarcinoma Primary liver cancer Develops from the bile ducts Arises from the cells lining the bile ducts Can arise anywhere in the biliary tree • • • • Intrahepatic Perihilar (Klatskin) Extrahepatic Gallbladder Can arise anywhere in the biliary tree • • • • Intrahepatic Perihilar (Klatskin) Extrahepatic Gallbladder Intrahepatic cholangiocarcinoma (ICC) • Located within the liver • Aggressive disease • Incidence increasing in many Western countries 2016 Saha et al. Forty-Year Trends in Cholangiocarcinoma Incidence in the U.S.: Intrahepatic Disease on the Rise. The Oncologist. 21:1–6 Intrahepatic cholangiocarcinoma (ICC) Genetics changes contributing to the development of ICC are not fully understood Mutations in many wellstudied genes have been noted Unique compared to mutations in extrahepatic cholangiocarcinoma & gallbladder cancer • Oncogenes: Kras, IDH1, IDH2 • Tumor suppressor genes: p53, BAP1, PBRM1 Gene Extrahepatic Intrahepatic 2015 Teh et al Pathogenesis of CCA genetics to signaling pathways Best Practice & Research Clinical Gastroenterology 29, 233-44 Molecular alterations in ICC BAP1 Encodes a protein involved in DNA remodeling 1. Renal cell carcinoma 2. Uveal melanoma 3. Malignant mesothelioma Studying cancer • Discovery of tumor-specific targets, like mutations in BAP1, is required to improve detection and treatment of cancer at earlier stages • Cancer models helps make these discoveries ▫ In vitro models ▫ In vivo models In vitro models Limitations • AnimalAdvantages: and human cancer cell lines • Used to study how different pathways in these Selection when Discovery of adapting to in molecular cells work vitro conditions mechanisms : Controlled conditions Mutations can arise over time Homogeneity Homogeneous population Reproducibility No TME In vivo models • Animal models that mimic the natural history of human cancers and their clinical response to therapy In vitro In vivo 2014 Cekanova and Rathore. Animal models and therapeutic molecular targets of cancer: utility and limitations. Drug Design, Development and Therapy 8: 1911-22 Mouse models Chemically-induced mouse models of cancer Xenografts Genetically engineered mouse models (GEMMs) of cancer GEMMs Carry mutations in genes that are associated with specific human diseases → mimic the diseases Can be used as experimental and preclinical model systems Classified as transgenic or endogenous Questions? Overview Background • Intrahepatic cholangiocarcinoma and BAP1 • How we study cancer • Mouse models • The KPC mouse An example ICC and BAP1 • Existing ICC models • BAP1 GEMM development Pancreatic cancer • Most commonly pancreatic ductal adenocarcinoma (PDAC) • Many things in common with ICC… ▫ Aggressive disease ▫ Increasingly common cause of death in the United States • Several GEMMs of pancreatic cancer have been developed The KPC mouse • Expression of oncogenic Kras and mutant p53 in all cells of the pancreas GEMMs Carry mutations in genes that are associated with specific human diseases → mimic the diseases Can be used as experimental and preclinical model systems Classified as transgenic or endogenous The KPC mouse • Expression of oncogenic Kras and mutant p53 in all cells of the pancreas 2013 Harno et al. Metabolic pitfalls of CNS Cre-based technology. Cell Metabolism 18: 21-28 The KPC mouse • Expression of oncogenic Kras and mutant p53 in all cells of the pancreas • Most widely used of all pancreatic cancer GEMMs • Genetically and histopathologically similar to human pancreas cancer Genetically similar… Histopathologically similar… 2015 Gopinathan et al. GEMMs as preclinical models for testing pancreatic cancer therapies. Dis Model & Mech 8, 1185-1200 The KPC mouse • Expression of oncogenic Kras and mutant p53 in all cells of the pancreas • Most widely used of all pancreatic cancer GEMMs • Genetically and histopathologically similar to human pancreas cancer • Successfully used to study different strategies for targeting PDAC including early detection, prevention & treatment Overview Background • Intrahepatic cholangiocarcinoma and BAP1 • How we study cancer • Mouse models • The KPC mouse An example ICC and BAP1 • Existing ICC models • BAP1 GEMM development PDAC and ICC share many features Multi-stage progression from normal tissue to invasive cancer Tumors surrounded by dense connective tissue Early invasion and spread Late detection / diagnosis → limited treatment options ICC cont. Genetics changes contributing to the development of ICC are not fully understood Mutations in many wellstudied genes have been noted Unique compared to mutations in extrahepatic cholangiocarcinoma & gallbladder cancer • Oncogenes: Kras, IDH1, IDH2 • Tumor suppressor genes: p53, BAP1, PBRM1 ICC cont. Genetics changes contributing to the development of ICC are not fully understood Mutations in many wellstudied genes have been noted Unique compared to mutations in extrahepatic cholangiocarcinoma & gallbladder cancer • Oncogenes: Kras, IDH1, IDH2 • Tumor suppressor genes: p53, BAP1, PBRM1 Current ICC GEMMs 1. Activating mutation of Kras + deletion of p53 ▫ Multistage progression of ICC ▫ Premalignant biliary lesions Development of stroma-rich tumors Genetically & histopathologically faithful model of ICC 2012 O'Dell et al. KrasG12D and p53 mutation cause primary intrahepatic cholangiocarcinoma. Cancer Res 72(6), 1557–67 Current ICC GEMMs 2. Activating mutation of Kras + mutant IDH2 ▫ Multistage progression of ICC Liver cell expansion Premalignant biliary lesions ▫ Model of ICC that provides a functional link between mutation and cancer 2014 Saha et al. Mutant IDH inhibits HNF-4a to block hepatocyte differentiation and promote biliary cancer. Nature 513(7516), 110-4 ICC cont. Genetics changes contributing to the development of ICC are not fully understood Mutations in many wellstudied genes have been noted Unique compared to mutations in extrahepatic cholangiocarcinoma & gallbladder cancer • Oncogenes: Kras, IDH1, IDH2 • Tumor suppressor genes: p53, BAP1, PBRM1 ICC cont. Genetics changes contributing to the development of ICC are not fully understood Mutations in many wellstudied genes have been noted Unique compared to mutations in extrahepatic cholangiocarcinoma & gallbladder cancer • Oncogenes: Kras, IDH1, IDH2 • Tumor suppressor genes: p53, BAP1, PBRM1 Development of a new ICC GEMM • Activating mutation of Kras + deletion of BAP1 Molecular alterations in ICC BAP1 Encodes a protein involved in DNA remodeling Development of a new ICC GEMM • Activating mutation of Kras + deletion of BAP1 Development of a new ICC GEMM • Activating mutation of Kras + deletion of BAP1 • Multistage progression of ICC including premalignant lesions ▫ Genetically and histopathologically faithful Development of a new ICC GEMM Development of a new ICC GEMM – Future directions • Activating mutation of Kras + deletion of BAP1 • Multistage progression of ICC including premalignant lesions ▫ Genetically and histopathologically faithful • Determine functional link between BAP1 mutations and ICC • Use as a preclinical model to study different strategies for detecting and treating ICC Overview Background • Intrahepatic cholangiocarcinoma and BAP1 • How we study cancer • Mouse models • The KPC mouse An example ICC and BAP1 • Existing ICC models • BAP1 GEMM development Conclusions ICC is a cancer of the bile ducts that currently has limited treatment options BAP1 is involved in DNA remodeling and has an incompletely understood role in ICC GEMMs mimic human cancers • Used as experimental & preclinical models BAP1-mutant GEMMs can improve our understanding of ICC • May result in improved detection and treatment of ICC in humans Further questions • Rebecca Marcus, MD ▫ [email protected] • http://cholangiocarcinoma.org/ Thank you for attending (and interacting)! • A recording of this Webinar will be available at http://cholangiocarcinoma.org/videos/ • Powerpoint slides also available online References Cekanova and Rathore. Animal models and therapeutic molecular targets of cancer: utility and limitations. Drug Design, Development and Therapy. 2014,8: 1911-22 Gopinathan et al. GEMMs as preclinical models for testing pancreatic cancer therapies. Dis Model & Mech. 2015,8: 1185-1200 Harno et al. Metabolic pitfalls of CNS Cre-based technology. Cell Metabolism. 2013,18: 21-28 O'Dell et al. KrasG12D and p53 mutation cause primary intrahepatic cholangiocarcinoma. Cancer Research. 2012,72(6): 1557–67 Saha et al. Forty-Year Trends in Cholangiocarcinoma Incidence in the U.S.: Intrahepatic Disease on the Rise. The Oncologist. 2016,21: 1–6 Saha et al. Mutant IDH inhibits HNF-4a to block hepatocyte differentiation and promote biliary cancer. Nature. 2014,513(7516): 110-4 Teh et al Pathogenesis of CCA genetics to signaling pathways. Best Practice & Research Clinical Gastroenterology. 2015,29: 233-44 BAP1 PBRM1
