Microtubule stabilizers, including the taxanes paclitaxel and docetaxel, are a mainstay in the treatment of solid tumors, including breast and ovarian cancers. Although these agents are often effective as first-line therapy, they are susceptible to common drug resistance mechanisms, including the upregulation of drug efflux pumps. Therefore, there is a critical need to develop novel classes of microtubule targeted agents that retain activity in taxane-resistant settings. The C22,23-epoxy taccalonolides are a class of plant-derived microtubule stabilizers that covalently and irreversibly bind microtubules, allowing them to retain efficacy in a variety of taxane-resistant cancer models. We employed cellular-based binding studies to fully map the taccalonolide pharmacophore and confirm the target specificity of this covalent compound. The identification of β-tubulin residues that are critical for taccalonolide binding in a cellular context has provided the opportunity to generate functional taccalonolide mimetics through a synthetically tractable approach.
Herein, we demonstrate that taccalonolide AF is less susceptible to p-glycoprotein-mediated drug efflux than paclitaxel in two separate ovarian cancer models and that it has superior cellular persistence after drug washout, likely due to irreversible target engagement. While taccalonolide AF demonstrated potent and persistent in vivo antitumor efficacy against the taxane-resistant NCI/ADR-RES ovarian cancer model as a flank xenograft when administered systemically, it was associated with a narrow therapeutic window. Additional studies showing that intratumoral injection of the taccalonolides into flank tumors provided long-term antitumor efficacy months after the final dose prompted a study of their utility in the targeted delivery to a disseminated orthotopic ovarian cancer model representing localized metastasis. Indeed, we found that taccalonolide-treated animals showed a significant decrease in micrometastasis of taxane-resistant ovarian cancer cells to the spleen, as detected by quantitative RT-PCR, without any evidence of systemic toxicity. We propose that the irreversible mechanism of microtubule stabilization elicited by the taccalonolides has the unique potential for intraperitoneal treatment of locally disseminated taxane-resistant disease, which represents a significant unmet clinical need in the treatment of ovarian cancer patients.
This research was funded by R01 CA219948 and the Voelcker Young Investigator Award to A.L.R. Training for S.S.Y. was provided by a predoctoral fellowship from the Cancer Prevention amp;amp; Research Institute of Texas (CPRIT)-funded Research Training Award (RP 170345).
