Evaluating The Efficacy Of A Novel Class Of Covalent Microtubule Stabilizers In Taxane Resistant Ovarian Cancer

Ovarian cancer has few targeted therapies and high rates of metastasis. Taxane microtubule stabilizers, including paclitaxel, are a mainstay in the treatment of adult solid tumors as single agents and in combination with other cytotoxic chemotherapies, targeted therapies, and immunotherapies. The standard of care for ovarian cancer patients comprises of combination chemotherapy consisting of a taxane with a platinum agent administered intravenously or intraperitoneally. Although this approach is highly effective initially, up to 70% of ovarian cancer patients will acquire taxane resistance. Therefore, it is essential to identify drugs that retain efficacy in clinically relevant models of taxane resistance, including those with elevated P-glycoprotein (Pgp) expression. The development of a microtubule stabilizer that retains efficacy in taxane resistant ovarian cancer would be optimal since microtubule disruption is proven to be an effective target in this disease. The taccalonolides are a novel class of covalent and irreversible microtubule stabilizers that circumvent clinically relevant forms of taxane resistance in vitro and in vivo breast cancer models. However, the taccalonolides have a narrow therapeutic window and short serum half-life that would benefit from a more targeted delivery. We hypothesized that localized intraperitoneal delivery of the taccalonolides in ovarian cancer models may be an optimal strategy for the treatment of intraperitoneally disseminated disease. We have found that the taccalonolides are less susceptible than paclitaxel to Pgp-mediated drug resistance in a human ovarian cancer cell line model. Additional experiments have demonstrated that the taccalonolides retain long-term antiproliferative and cytotoxic efficacy following acute treatment of human and murine ovarian cancer cells, demonstrating superior cellular persistence as compared to other classes of microtubule stabilizing drugs. We are currently evaluating the efficacy of the taccalonolides in ovarian cancer models using localized, intraperitoneal administration in a syngeneic and orthotopic murine model, which may be optimal for delivery of this irreversible microtubule stabilizer. Citation Format: Samantha S.M. Yee, Lin Du, April L. Risinger. Evaluating the efficacy of a novel class of covalent microtubule stabilizers in taxane resistant ovarian cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3000.