Titles and Affiliations
President, Helen Diller Family Comprehensive Cancer Center
Senior Vice President for Cancer Services, UCSF Health
Professor of Medicine, Division of Hematology/Oncology
Research area
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 experience tumor 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. 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 block xCT. Over the past year, the team confirmed that these drugs do, in fact, affect xCT activity and explored how they act. Dr. Ashworth and his team are currently developing new tools to investigate xCT function. In a separate line of work, the team found that combining two existing drugs can lower the levels estrogen receptor alpha (ERa) and its mutant forms. This finding is important because tumors that resist hormone therapy often depend on ERa. This drug combination might be useful for treating cancers that are resistant to hormone therapies. The team also performed computational analysis to identify a genetic pattern that could help predict which tumors are likely to respond to this treatment.
What’s next
Over the next year, Dr. Ashworth’s team will leverage their reporter protein platform to perform additional drug screens. These efforts will focus on inhibitors that can achieve high selectivity, thus reducing off-target effects. They will also use advanced modeling techniques to design proteins that can bind and block xCT.
Biography
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.
