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Epigenome-targeted therapy for cholangiocarcinoma.

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Epigenetics: the Achilles heel of bile duct cancer?

Cholangiocarcinoma (CCA) or bile duct cancers are a rare heterogeneous group of malignancies with extremely poor prognosis. With most patients surviving less than a year after standard chemotherapy, there is an imminent need for novel treatments.

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Accumulating evidence indicates the existence of epigenetic mutations in CCA, suggesting that epigenetic regulators are linked to tumour growth. These enzymes are responsible for switching genes on and off in the entire genome, a process that can be reversed using certain drugs, thus opening new avenues for the treatment of CCA. However, to streamline epigenome-driven therapy to the clinic, there is a need to determine the molecular and cellular responses to epigenetic manipulation. The epigenetic landscape of CCA With the support of the Marie Curie programme, the EpiTarget project aimed to investigate CCA epigenetics further and identify novel therapeutic targets. To address CCA heterogeneity, partners performed a genome-wide study on over 200 CCA patient samples. Researchers obtained an extensive dataset, only possible through close collaborations with organisations such as the European Network for the Study of Cholangiocarcinoma. “Data sharing is fundamental to obtaining sufficient patient numbers to identify and adequately test all future therapeutics,″ emphasises project coordinator Associate Professor Jesper B Andersen. Widespread deregulation of various epigenetic regulators was discovered, and researchers mapped the global consequences. Intriguingly, the identified epigenetic alterations of bile duct tumours compared to normal tissue were associated with cancer-related processes. As Dr Andersen explains “the altered epigenome of CCA may explain, in part, the aberrant signalling detected in tumours.″ Most importantly, treatment of CCA cells with epigenetic drugs stopped cell division. Towards precision medicine When it comes to highly heterogeneous diseases such as CCA, precision medicine approaches must be implemented, where treatment of patients is based on a common molecular alteration. Clinical trials testing drugs should therefore follow a similar approach, grouping patients according to their molecular profile to obtain meaningful results. EpiTarget contributed to precision medicine in CCA by identifying a highly interesting therapeutic target that is overexpressed in a specific subset of CCA patients. This target seems to influence the folding of DNA inside the nucleus. “An inhibitor of this target, already tested in advanced clinical trials for a different disease, may offer an alternative treatment for CCA,” comments the Marie-Curie fellow Dr O’Rourke. Currently there is no curative treatment available for CCA and most patients are administered palliative chemotherapy. According to Dr Andersen, the idea is to administer this inhibitor to sensitise the tumour to chemotherapy – alone it is not sufficient to kill the tumour cells. Given that standard chemotherapy only temporarily slows tumour progression, EpiTarget researchers in collaboration with the University of Helsinki, screened over 500 drugs already on the market for alternative clinical conditions. Many of these drugs demonstrated efficacy in different subsets of CCA, and the Andersen group is currently working to identify the drug that provides the optimum synergistic effect with the epigenetic inhibitor. CCA mortality rates are escalating among both sexes in the EU due to risk factors associated with modern lifestyle such as alcohol consumption and non-alcoholic fatty liver disease. Dr Andersen is confident that “the findings of EpiTarget comprise a turning point in our view of the molecular architecture of this devastating malignancy, offering promising new therapies.″

Keywords

EpiTarget, cholangiocarcinoma (CCA), epigenome, chemotherapy, epigenetic inhibitor

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