Expanding the Therapeutic Window of PI3K Inhibitors to Treat Triple-Negative Breast Cancer
Abstract
Lack of targeted therapeutic options is a major setback for the clinical care of triple negative breast cancer (TNBC) patients. As a potential targeted therapy for TNBC, a group of drugs termed PI3K inhibitor have shown significant potential in clinical trials but are also plagued with low responses and severe toxicity. The obvious obstacle for the implementation of these promising cancer drugs in clinical patient care is to find a means to expand their therapeutic window by improving the response of TNBC to these drugs and by minimizing their toxicity. Genetic and epigenetic variations contribute to drug responses. Unlike genetic variation, epigenetic changes are reversible and therefore provide an opportunity to improve drug response by targeting relevant epigenetic regulators. This research proposes to use vitamin C, as an epigenetic regulator and an adjuvant, to improve the therapeutic outcome of PI3K inhibitors. Therefore, this research addresses the overarching challenge of Revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival. Our preliminary results showed that vitamin C indeed significantly sensitized TNBC cells to pan-PI3K inhibitor buparlisib, which has been largely phased out of TNBC clinical trials. Aiming to translate our findings to the clinical care of patients, this study will primarily focus on the FDA-approved PI3K-alpha specific inhibitor alpelisib, which is under investigation in ongoing TNBC clinical trials. Using vitamin C as an adjuvant to sensitize TNBC cells, lower doses of alpelisib could then conceivably be used to achieve an increased therapeutic index, which will translate to a reduced side-effect profile in patients. Vitamin C is safe, readily available, and translational to patient care. If successful in rigorous preclinical tests as proposed, this study can be moved forward to clinical settings to test if vitamin C could improve the benefit/toxicity ratio of alpelisib in the treatment of TNBC patients. Overall, this research could develop a translational therapeutic strategy and help accelerate the implementation of alpelisib into the treatment of TNBC patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210029
Entities
People
- Gaofeng Wang
Organizations
- United States Army
- University of Miami