Dynamic changes in FANC protein expression in ovarian cancer– impact on chemosensitivity and resistance

This 3-year PhD studentship funded by the Melville Trust is available to start in September 2019 at the Cancer Research UK Edinburgh Centre, which is part of the Institute of Genetics and Molecular Medicine (IGMM) at the University of Edinburgh. You should hold at least an upper second-class degree in a relevant subject and comply with the University of Edinburgh’s English language requirements.

Project details

The predominant form of ovarian cancer is high grade serous ovarian cancer (HGSOC) which accounts for 70% of ovarian cancers. The majority of patients initially respond to platinum-based therapy, but in 80-90% of cases, drug resistance will eventually emerge. Strategies are required to circumvent development of this resistance.

The goal of this project is to develop new insights into the roles of the Fanconi Anaemia (FANC) family of proteins in determining ovarian cancer drug responsiveness. The Fanconi Anaemia pathway repairs DNA interstrand crosslinks including those generated by platinum therapies; the FANC family consists of 19 members with a number of associated proteins. We have previously observed changes in FANC gene expression on chemotherapy treatment (Koussounadis, BJ Cancer, 110; 2975, 2014) and after the development of resistance (Macleod, Cancer Research, 65; 6789, 2005). We have also helped identify a novel member of the family (FANC P/SLX4) (Crossan, Nature Genetics, 43, 417, 2011) whose role in ovarian cancer has not previously been investigated.

This project aims to explore further important changes and defects in FANC proteins that impact on ovarian cancer chemosensitivity. It will investigate inhibitors that impact FANC function as potential therapeutics. The project will be carried out using a panel of human ovarian cancer cell line models that were obtained before and after drug resistance developed. It will employ a number of cellular and molecular approaches including cell culture, protein and DNA techniques and functional assays.

These results should help identify key FANC family members associated with chemosensitivity and chemoresistance and provide the basis for future targeted drug development.