OPTIMIZATION OF A NOVEL CLASS OF MICROTUBULE STABILIZERS

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