EpiTarget · Epigenome-targeted therapy for cholangiocarcinoma.

Epigenome-targeted therapy for cholangiocarcinoma.

Cholangiocarcinoma (CCA) comprise a family of rare orphan malignancies arising throughout the biliary tract. These cancers are typified by asymptomatic presentation, late diagnosis and extremely poor prognosis. The majority (70-90%) of CCA patients who are diagnosed with advanced disease, in addition to resected patients whose tumours recur, undergo chemotherapy with gemcitabine and cisplatin. This regimen is purely palliative, non-FDA-approved for CCA and median patient survival under this treatment regimen is less than 12 months. Overall, 0-5% CCA patients remain alive at 5 years post-diagnosis. Unlike other cancers, CCA incidence and mortality rates have increased among males and females in Europe and the wider world. Together, these atypical clinical trends indicate CCA patients comprise a growing demographic of society for whom modern healthcare can do little. Furthermore, even if robust biomarkers for early disease detection are discovered in the future, general population screening for this rare disease would be practically and economically infeasible. Therefore, it is evident that new therapeutic regimens are urgently needed for the majority of patients who present with advanced and metastatic disease. Initially, the interpretation of sequencing studies in CCA was somewhat bleak as they painted a picture of biliary tumours as highly heterogeneous malignancies with low-to-moderate mutation frequencies in ‘classic’ cancer-associated genes and identified significant proportions of patients with no mutations at all in such genes. However, these studies universally highlighted recurrent mutations in epigenetic regulators which, given their normal function in epigenome homeostasis, implicates extensive epigenome dysregulation in CCA. Epigenome-targeted therapy affords several advantages over mutation-based approaches, including the innate reversibility of epigenetic marks and the fundamental importance of epigenetic plasticity and remodelling to chemoresistance and metastasis. Accordingly, the objectives of this EpiTarget fellowship were to decipher the genomic and epigenomic landscapes of patient tumours and synergistically evaluate the therapeutic potential of clinically-tolerable epigenetic drugs in CCA.

Data: CORDIS, © European Union