The role of IDH mutation in liver cell plasticity and cancer

Cholangiocarcinoma (cancer of the bile ducts) is a highly aggressive liver cancer with currently no curative treatment options aside from major surgery, for which few patients are eligible. Cancers, including cholangiocarcinoma arise when DNA is damaged or mis-coded (mutations). This fellowship seeks to investigate the role that mutations in a gene known as IDH1 play in the development of bile duct cancer. Specifically I wish to discover whether a substance known as 2HG produced when IDH1 mutation occurs, is able to 're-programme' or change the identity of cells from liver cells (known as 'hepatocytes') into bile duct cells ('cholangiocytes') and whether this change promotes the formation of bile duct cancer. I wish to establish whether in fact IDH1 mutation occurs in liver cells or bile duct cells in disease and whether the mutation promotes local inflammation or toxic injury to cells which might be then targeted in designing new treatments.