Optimization of a novel class of microtubule stabilizers

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Microtubule stabilizing agents (MSAs) are some of the most widely used and effective therapies available for the treatment of solid tumors. However, their utility is compromised by innate and acquired drug resistance. The taccalonolides (taccas) are a mechanistically unique class of MSAs that circumvent multiple clinically relevant forms of drug resistance. Multiple potent taccas identified by our laboratories have effective antitumor activity in drug sensitive and resistant in vivo models but suffer from a narrow therapeutic window. This project will develop an in depth understanding of the pharmacokinetics and pharmacodynamics of this class of MSAs that will yield taccas with an optimal in vivo profile for future clinical development. The recent generation of a crystal structure of a tacca bound to tubulin heterodimers has provided unprecedented insight into the tacca pharmacophore, which will be used to experimentally define the critical residues on tubulin and moieties on the taccas that mediate their novel mechanism of microtubule stabilizing activity. We have also identified sites on the tacca skeleton that can be modified semi-synthetically to improve compound stability and optimize their pharmacokinetic profile and antitumor actions. Functional fluorescent and biotin-tagged taccas have been generated that will allow, for the first time, direct detection of the taccas in vitro and in vivo that will be instrumental in understanding the uptake, distribution, and target binding of this unique MSA. In addition to generating taccas with a more favorable pharmacokinetic profile and evaluating their efficacy in molecularly defined patient derived tumor xenograft and syngeneic models, we will also determine biomarkers associated with response to this novel class of MSAs. Expression analysis in a panel of molecularly defined triple negative breast cancer cell lines identified signaling pathways that correlate with the cytotoxic efficacy of the taccas. We will further evaluate whether intrinsic alterations in these signaling pathways are biomarkers of drug response and, reciprocally, follow up on data indicating that the taccas can also alter the functional consequences of these signaling pathways. These studies are significant in that they will lead, in the future, to the generation of a clinical lead candidate for the treatment of drug resistant solid tumors and a greater understanding of their mechanism of action and predictors of response.