Hayley McDaid, PhD

Identifying targeted therapies and novel combination approaches to decrease drug resistance and improve outcomes for patients with triple-negative breast cancer.

Impact

Therapeutics such as Taxol are indicated for first-line treatment of patients with triple-negative breast cancer (TNBC) and other subtypes of breast cancer. While many patients experience good outcomes to this treatment, some patients experience drug resistance, or relapse after a period of remission. In addition, some patients develop toxicities or experience long-term, debilitating side effects. The BCRF research led by Dr. McDaid is focused on characterizing cancer cells that survive anti-cancer therapy, specifically investigating the causes of resistance after therapy with drugs like Taxol. Her team has synthesized novel molecules that work like Taxol but are more effective at killing breast cancer cells in laboratory models. They are investigating the therapeutic efficacy of these molecules with the long-term goal of developing potent, less toxic Taxol-like drugs for use in advanced disease.

Progress Thus Far

Dr. McDaid and her colleagues have been working to develop synthetic analogs of naturally occurring chemicals called discodermolides. These Taxol-like chemicals can be isolated in minute quantities from sponges and can inhibit tumor growth. The team also found that these chemicals have distinct structural differences from taxol and this may account for their unique properties. Because they are available in such small quantities, Dr. McDaid’s group sought to develop synthetic versions in order to test the therapeutic potential of discodermolides. In related studies, they are examining cellular senescence—an underlying cause of relapse after chemotherapy. They showed that while senescent cancer cells do not divide, they do produce inflammatory proteins that can promote the growth of neighboring tumor cells, leading to recurrence or metastasis. She hypothesizes that the pattern of these proteins might serve as novel blood-based biomarkers or signatures of senescence and provide a strategy for tracking the process. In the last year, they identified a protein signature made up of 30 proteins that tracks with a therapeutic sequence: They were elevated post-chemotherapy and reduced after senolytic treatment. Parallel studies demonstrated that one of the engineered discodermolides potently induces tumor cell death. Further, for the cells that do not die, this discodermolide promotes a durable form of senescence unlike the more transitory state of senescence caused by most chemotherapies.

What’s next

Dr. McDaid will continue to optimize the use of discodermolides based on promising efficacy and safety results in breast tumor laboratory models and identify those that warrant pre-clinical development. They will also measure the dynamic changes in the protein signature they identified and assess its utility in identifying patients likely to benefit from adjuvant senolytic therapy. Expanding her investigation, Dr. McDaid will seek cell-surface enriched proteins in senescent cells that may be leveraged to produce anti-body drug conjugates, providing a novel senolytic therapeutic. The results of her studies will potentially expand the arsenal of strategies for treating breast cancer, particularly aggressive forms such as TNBC.