University of California, San Francisco San Francisco, California
President, Helen Diller Family Comprehensive Cancer Center Senior Vice President for Cancer Services, UCSF Health Professor of Medicine, Division of Hematology/Oncology
Identifying new therapeutic targets for aggressive forms of breast cancer.
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.
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.
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.
Alan Ashworth, PhD, FR, is President of the UCSF Helen Diller Family Comprehensive Cancer Center in San Francisco, a role he began in January 2015. He was previously Chief Executive of the Institute of Cancer Research (ICR) in London, United Kingdom.
In 1999 he was appointed the first Director of the Breakthrough Breast Cancer Research Centre where he was also Professor of Molecular Biology and leader of the Gene Function team. Professor Ashworth’s Directorship ended in January 2011 when was appointed Chief Executive of the ICR.
A translational biologist and laboratory researcher, Dr. Ashworth’s research focuses on understanding breast cancer genetics and applying what he learns to change the way patients are treated. He was a key part of the team that identified the BRCA2 breast cancer susceptibility gene, which is linked to an increased risk of some types of cancer. Ten years later, Dr. Ashworth found a way to kill off BRCA1- and 2-related tumor cells by treating them with PARP inhibitors, which amplifies the damage caused by the broken DNA repair machinery in those cells. This exemplifies the genetic principle of synthetic lethality in cancer therapy.
Dr. Ashworth is an elected member of EMBO and the Academy of Medical Sciences and a Fellow of the Royal Society. He has been the recipient of a number of scientific prizes and awards including The European Society of Medical Oncology Lifetime Achievement Award, the David T. Workman Memorial Award of the Samuel Waxman Cancer Research Foundation and the Meyenburg Foundation’s Cancer Research Award and was the inaugural winner of the 2013 Basser Global Prize. He has also recently been selected as the recipient of the 2015 Genetics Society Medal.
2008
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