Professor Robert Brown, Medicine (Brown Epigenetic Therapy) team
Epigenetic mechanisms regulate gene expression without involving gene mutations. Epigenetic silencing of tumour suppressor genes has a major role in the aetiology of human cancers. As well as affecting disease progression, epigenetic gene silencing influences response to treatment and drug resistance. Unlike gene mutations, such epigenetic change can be reversed using compounds that inhibit maintenance of epigenetic silencing and reactivate gene expression.
The Epigenetics Team are examining changes in the cancer epigenome to provide understanding of tumour development and response to treatment. We have shown that DNA methylation can provide an epigenomic signature of genes that predict survival of ovarian cancer patients following surgery and chemotherapy. For instance, we have systematically profiled DNA methylation at promoter CpG islands of Wnt pathway genes from epithelial ovarian cancer taken prior to treatment and shown that levels of methylation at multiple Wnt loci were associated with survival. The prognostic value of these methylation biomarkers is additional to the information provided by existing clinical prognostic markers. Such methylation biomarkers can then be used for patient stratification in clinical trials of novel therapies, including epigenetic therapies.
We have shown that there are a higher percentage of tumour sustaining cells that have stem cell like properties in ascites from patients that have relapsed following chemotherapy compared to chemo-naive patients, which is consistent with selection for this subpopulation during platinum-based chemotherapy. Furthermore, the histone methyltransferase EZH2, known to be involved in epigenetic regulation, shows consistently elevated expression in these tumour sustaining cells. Inhibition of EZH2 expression in experimental models leads to reduced tumour growth. Together these data support a key role for EZH2 in the maintenance, during chemotherapy, of a drug-resistant tumour-sustaining subpopulation of cells in ovarian tumours that can lead to acquired drug resistance, and as such, is an important target for anticancer drug development.