Grant: Project Grant

Microtubules (MTs) are protein polymers that form a cable-like network of transport super-highway to move important cargoes around inside a cell. One of these cargoes is our chromosomes, the genetic material that makes us what we are. It turns out that these cables need to grow and shrink all the time to perform their functions such as capturing and transporting chromosomes, especially when cells are dividing. A clinically proven strategy to stop cancer cell proliferation is to perturb the growing and shrinking dynamics of MT polymers. In fact, MT-targeting drugs are among the most successful chemotherapeutic agents currently used in the clinics. However, their success is hindered by adverse side effects and the development of drug resistance in cancer patients. To address these shortcomings, we propose to further exploit this proven approach through an alternative route - by targeting the protein enzymes that control the MT polymers. Using a high-throughput screening approach, our lab has already identified chemical agents that modulate these MT modifying enzymes. Importantly, these agents exert a potent growth suppressive effect on cancer cells, but seem to spare non-cancer cells. However, the precise molecular mechanism how these molecules work is still not known. In the proposed project, we aim to use modern cutting-edge technologies to understand the following: 1) How these chemical agents affect the MT-regulating enzymes at the molecular level; 2) how this in turn affects cancer cell proliferation; and 3) how to improve the specificity and efficacy of this new class of potential chemotherapeutics. Our ultimate goal is to validate this new strategy in order to develop the next generation anti-cancer drugs.