Alan Ashworth, PhD, FRS

Identifying new therapeutic targets for aggressive forms of breast cancer.

Impact

Triple-negative breast cancer (TNBC) is an aggressive disease with poor prognosis. Although TNBC patients benefit from standard chemotherapy, and some fare well with new immunotherapies, overall, they face high recurrence rates and are more likely to develop chemoresistance. There is therefore an urgent need to develop new targeted therapies for these patients.

Progress Thus Far

Dr. Ashworth and his team identified a protein called xCT as a potentially promising therapeutic target for TNBC. This protein serves as a molecular transporter; it sits within the outer membranes of cells, funneling specific molecules into the cell and expelling others. Tumor cells can use it to eject chemotherapies and take in nutrients to support growth. While it is dispensable for the function of healthy cells, loss of xCT function is lethal to tumor cells, making it an attractive therapeutic target. Importantly, xCT is present in approximately half of TNBC tumors and high levels are associated with worse outcomes for patients. The team engineered a novel reporter protein to test whether candidate drugs effectively blocking xCT. Investigations over the past year have revealed that at least one of these compounds blocks xCT activity. In parallel, Dr. Ashworth and team have successfully developed novel antibodies that target and bind to xCT. Analyses of promising candidates in both blocking and binding studies are ongoing.

What’s next

Over the next year, Dr. Ashworth’s team will continue to characterize top hits from their preliminary drug screens and to identify additional hits by screening larger libraries. The team is also continuing to improve the design of antibodies that bind to xCT and finding new antibodies and proteins that can bind and block xCT.