Here we propose to study two injectable formulations that provide different delivery routes for Talazoparib, potent PAPR inhibitor: An implant, InCeT-Talazoparib, which can be injected directly in the tumor where it will act as a sustained release depot of Talazoparib over a prolonged period of approximately 30 days. It delivers 100% of the drug to the tumor site with almost no systemic toxicity. It can be used for neoadjuvant chemotherapy or as a breast-preserving alternative to radical mastectomy. Our central hypothesis is that these Talazoparib formulations will enhance tumor drug delivery compared to oral Talazoparib, thereby increasing tumor cell kill and minimizing side-effects in triple-negative breast cancer. To prove this hypothesis, we will study how these formulations behave in the bloodstream, where they end up, and how long they last. The therapeutic efficacy will be assessed in vitro using mutated BC cell lines and in vivo using genetically engineered and orthotopic mouse models. Drug accumulation, uptake, safety, and efficacy at the cell, tissue, and animal level will be compared to conventional oral dosing of Talazoparib. Successful outcome of the proposed studies could lead to Phase I clinical trials for neoadjuvant treatment of BC in 2-3 years. If successfully completed, the project would proffer new treatment options for enhancing therapeutic efficacy, prolonging progression-free survival, reducing mortality, and greatly improving the quality of life for as many as 75% of TNBC patients, and 33% of breast cancer patients overall.
