Abstract P2-24-01: The development of covalent microtubule stabilizers for drug-resistant cancers

Abstract

Abstract Microtubule targeting agents (MTAs) are some of the most commonly used and effective chemotherapeutic agents used in the treatment of breast cancer and other solid tumors. Clinically approved MTAs include microtubule destabilizers, such as the vinca alkaloids or eribulin, as well as the taxane class of microtubule stabilizers, including paclitaxel. While MTAs are effective chemotherapeutics, the development of resistance due to drug efflux or changes in β-tubulin isotype expression are major clinical limitations to each the currently approved drugs of this class. One strategy for overcoming drug resistance is the development of drugs that covalently bind to their drug target, which has been validated in the clinic with the success of irreversible EGFR inhibitors in drug resistant non-small cell lung cancer. We have identified the C22,23-epoxytaccalonolides (taccas) as a class of plant-derived microtubule stabilizers that covalently bind to β-tubulin with a high degree of specificity and retain efficacy in drug-resistant models in vitro and in vivo. Although the taccas have potent and persistent antitumor efficacy in vivo, they suffer from a narrow therapeutic index and short serum half-life that provides optimal efficacy when targeted directly to the tumor site. We are undertaking a multipronged approach to generate synthetic tacca analogs (taccalogs) that retain the efficacy of the natural product with improved pharmacokinetic properties, including improved serum binding, to increase half-life and provide better in vivo tolerability. We are also identifying strategies to improve tumor targeting of the taccas, which is being guided by determining their in vivo distribution with radiolabeled analogs. In a complementary approach, we tested the hypothesis that non-covalent microtubule stabilizers that have increased binding affinity to tubulin share properties with the taccas, such as the ability to circumvent drug resistance and provide potent and persistent in vivo efficacy with a more tolerable therapeutic window. Our data suggest that while non-covalent microtubule stabilizers with improved binding compared to paclitaxel provide improved cellular persistence after drug washout and potent antitumor efficacy, they are not able to overcome drug resistance to some degree as covalent inhibitors, demonstrating the advantage of continuing to develop irreversible drugs such as the taccalonolides for the treatment of drug resistant disease. Citation Format: Jacob N. Essif, April Risinger. The development of covalent microtubule stabilizers for drug-resistant cancers [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-24-01.