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 thereby leading to recurrence, or metastasis. Dr. McDaid’s team has found that one of the engineered discodermolides potently induces tumor cell death. And unlike the more transitory state of senescence caused by most chemotherapies, discodermolide-treated breast cancer cells that do not die undergo a durable form of senescence. Dr. McDaid has been working to optimize the use of discodermolides in breast tumor laboratory models and, so far, they show promising efficacy and safety against breast cancer.

What’s next

Dr. McDaid will continue to test discodermolides to identify those that warrant pre-clinical development. Dr. McDaid and her colleagues will also harness the most prominent feature of senescent cells–their ability to secrete high quantities of protein that are detectable in human blood and other fluids. In laboratory models of breast cancer, they have identified a cohort of senescence-enriched proteins from plasma that increase after chemotherapy. Ongoing experiments will investigate if candidate proteins are senescent-specific and, if so, do they provide proteomic signature of senescence that can help to develop novel senolytic therapies. The results of her studies will potentially expand the arsenal of strategies for treating breast cancer, particularly aggressive forms such as TNBC.