Grant: Collaborative Health Research Projects (NSERC partnered)

"Paclitaxel (PTX) is an antimitotic, microtubule-targeting agent that is highly active in the treatment of breast cancer. Combination therapy involving PTX or its mimics have has become a standard of care, however they are far from optimal therapeutics. They are limited by acquired and intrinsic tumor resistance, the risk of hypersensitivity reactions, and dose-limiting neurotoxicity. This has established the need for novel agents that act on the microtubules. Unfortunately, next generation agents target the same binding site on tubulin, and provide only limited solutions to these problems. Our research team has defined the first new druggable site on the microtubule lattice, since the discovery of the PTX in the 1970's. Using novel structural and computational techniques, we have generated a high resolution model of microtubules stabilized by a metabolite from deep sea sponges (laulimalide). Laulimalide has demonstrated efficacy in cell lines resistant to PTX, while class-resistant mutants retain sensitivity to the taxoids. This ''orthogonal'' property of laulimalide, in addition to its synergy with PTX, strongly favors the development of a new class of antimitotic agents. We propose to design and synthesize libraries of analogs based on our preliminary assessment of the pharmacophore, and to evaluate these analogs in biochemical and cellular assays relevant for the assessment of antimitotic compounds. Significantly, we will target the development of agents that maintain orthogonality, by guiding lead development towards cancers poorly managed by PTX (e.g. pediatric leukemias, pancreatic cancer). Additionally, the translational elements of the program will support testing of lead compounds in relevant models for toxic neuropathies. The innovation of this program derives from a novel entrypoint into mitotic regulation and the development of agents that support rather than compete with PTX in a clinical setting. The program brings together researchers in chemical biology, computational physics and natural product synthesis and combines them with leading clinical oncologists and experts in toxicological profiling. To facilitate the transition from basic research the team will be supported by the Alberta Cancer Clinical Research Unit (ACCRU). Early consultation with ACCRU will support seamless progression from research to appropriate phase 1 clinical trials. "