Professor Robert Brown

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.

Robert Brown is Professor of Translational Oncology and has a joint post between Imperial College London and The Institute of Cancer Research (ICR). He is Principal Investigator of the Cancer Research UK research programme, Pharmacodynamics and Drug Resistance, and is Co-Principal Investigator in the Ovarian Cancer Action Research Centre.

Professor Brown works on epigenetics and drug resistance research, with a particular focus on ovarian cancer. Working closely with clinical trials groups, in particular the Scottish Gynaecological Clinical Trials Group, he and his team have shown that in ovarian cancer, aberrant DNA methylation and epigenetic silencing of genes in tumours before chemotherapy can predict response to chemotherapy, while acquired methylation of other genes at the time of relapse following chemotherapy is associated with patient survival. He facilitates preclinical analysis and clinical trials of compounds which can reverse epigenetic silencing, and is using molecular biomarker assays to aid the clinical use of these compounds. Furthermore, he is identifying cancer specific epigenetic changes and developing novel compounds which target these changes. Recently, he has initiated studies on identifying such targets in ovarian tumour stem/sustaining cells.

He is a member of the Cancer Research UK New Agents Committee, Cancer Research UK Biomarker & Imaging Discovery & Development Committee, and the Leukaemia & Lymphoma Research Clinical Trials Committee. He is also Chair of the National Cancer Research Institute (NCRI) Biomarker and Imaging Clinical Studies Group.

He graduated from Edinburgh University with a BSc in Biological Sciences and did his PhD at the Medical Research Council (MRC) Radiobiology Unit, Harwell. Following a Postdoctoral Fellowship at the German Cancer Research Centre Heidelberg, he worked at the Beatson Laboratories Glasgow for many years, becoming Director of Laboratory Research in the Centre for Oncology and Applied Pharmacology, Glasgow University, before moving to his current post.