Endocrine Abstracts

Epigenetic events, such as gene promoter DNA hypermethylation linked to changes in gene expression, are causative of resistance to cytotoxic chemotherapy drugs such as cisplatin in ovarian cancer cell line models, and associated with response to chemotherapy and survival of high grade serous ovarian cancer patients. We are studying the role of epigenetic change throughout the patient journey and how this associates with gene expression changes which can be selected for during treatment to give rise to drug resistance. Based on these studies we propose that epigenetic change in tumours, potentially caused by DNA damage and repair, generates diversity and gene expression states that can rapidly evolve through drug treatment in a multi-step process, with the consequence in patients of acquired resistance and treatment failure. As an example, inactivation of the DNA mismatch repair gene MLH1 by DNA methylation leads to replication bypass and platinum damage tolerance, which can be reversed by DNA demethylating agents. These studies have led to clinical trials of epigenetic therapies as potential tumour chemosensitisers, with biomarkers inherent to the trial design. Current trials have demonstrated the importance of identifying less toxic agents, rational approaches to drug combinations and the need for appropriate stratification biomarkers. To address this we are evaluating novel histone deacetylase (HDAC) and histone methyltransferase (HKMT) inhibitors with associated biomarkers and initiated ChIP-Seq studies of histone marks in patient derived tumours.