Title: Mechanisms of Drug Resistance and Epigenetic Regulation
Funder: Cancer Research UK

Abstract: Background_x000D_ Drug resistance is a major obstacle to the successful treatment of cancer. Understanding mechanisms of drug resistance, and how they emerge, will be important for novel strategies to improve the treatment of cancer patients. Epigenetic mechanisms, including DNA methylation, are important drivers influencing chemo-responsiveness of tumours and acquired drug resistance, although we still have a poor understanding of how aberrant DNA methylation occurs in tumours. Although drug resistance can be overcome using epigenetic therapies in experimental models, clinical studies have highlighted the challenges of current epigenetic therapies for solid tumours and the need to identify more targeted approaches._x000D_ _x000D_ Aims and objectives_x000D_ • We will examine whether DNA damage repair causes aberrant DNA hypermethylation in endogenous sequences in tumours and investigate whether DNA mismatch repair influences DNA methylation during acquisition of drug resistance and/or at sites of DNA damage. _x000D_ • We have shown the potential of DNA methylation of Wnt pathway genes in determining clinical outcome in epithelial ovarian cancer (EOC). We will investigate correlation between epigenetic regulation of Wnt pathways (and other emerging prognostic pathways epigenetically regulated), clinical outcome, and pathway function in EOC._x000D_ • We will characterise candidate drivers of cisplatin resistance in EOC by investigating functional effects on chemosensitivity and methylation changes occurring in matched tumours and plasma before and after chemotherapy._x000D_ • Histone methyltransferases (HKMTs) have a key role in the maintenance of drug-resistant tumour-sustaining (stem cell) subpopulation of cells. We will investigate the phenotypic consequences of HKMT inhibition in ovarian tumour cells and sustaining subpopulations._x000D_ _x000D_ Our approach will remain translational: identifying validated targets and novel therapy strategies which can be taken through experimental models into clinical studies. We will focus on ovarian cancer; although as appropriate include collaborative studies on other tumour types._x000D_ _x000D_ Methods_x000D_ We will place emphasis on identifying clinically relevant biomarkers in well annotated tumour samples. To understand function of biomarkers we will use ovarian cell lines and cells grown ex vivo directly from patient tumour, as well as cell subpopulations isolated by flow cytometry. We will use a variety of established methods of epigenetic analysis, including bisulphite sequencing, differential methylation hybridization, ChIPseq, SiRNA knock-down amongst others. _x000D_ _x000D_ How results will be used_x000D_ Our long-term aims are to characterise epigenetic changes that affect tumour progression and acquired drug resistance, and that can inform clinical trial designs using stratification biomarkers and identify targets for novel therapeutic approaches to improve patient survival.


Research activity codes: 5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS