PRH/HHEX in intrahepatic cholangiocarcinoma, disease progression and response to chemotherapeutics.

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Cholangiocarcinoma is cancer of the bile ducts that carry bile from the liver to the gall bladder and the small intestine. The number of cases of Cholangiocarcinoma is increasing year by year as is the number of deaths caused by this disease. There are several established risk factors for Cholangiocarcinoma including chronic Hepatitis B and C infection, autoimmune-related diseases such as Primary Sclerosing Cholangitis (PSC), and, in some countries, liver fluke infection. In most cases the disease is very advanced at the time of diagnosis and only around 30% of patients are suitable for surgery. New treatment options and biomarkers that allow early detection and/or inform personalised cancer treatment for individual patients are urgently needed. Under normal circumstances cell proliferation, cell-cell contacts and cell movement are carefully controlled and a large part this control is brought about by proteins called transcription factors that determine which genes are turned on or off in our cells and thereby determine how each cell behaves. We are studying a transcription factor called PRH/HHEX that is essential for liver and bile duct formation because this factor can inhibit many important pathways in the cell that are known to be required for cancer cell division and movement. In this project we will investigate the importance of PRH in cholangiocarcinoma. Using samples taken from patients with cholangiocarcinoma we have already shown that PRH levels are reduced in cholangiocarcinoma cells. The aim of this project is to investigate this in more detail using a larger number of samples. We will also identify genes that are regulated by PRH in cholangiocarcinoma cells and we will determine whether the products of these genes, or PRH itself, can be used as biomarkers to predict how quickly the cancer will progress or even allow us to identify people at risk of developing cholangiocarcinoma before they show symptoms of the disease. We will also determine whether changes in PRH activity alter the ability cholangiocarcinoma cells to form tumours in mice and we will examine whether changes in PRH these cells makes them more or less sensitive to drugs that are used to treat this disease. Finally we think that the re-establishment of PRH activity in cholangiocarcinoma could be a useful strategy for cancer treatment. We will test this using drugs that prevent protein modifications that we have previously shown to result in PRH inactivation and PRH degradation.