Grant: Foundation Grant

Effective cancer therapy exploits specific biological differences between cancer cells and normal cells. Cancer cells often have defects that reduce the efficiency of chromosome transmission. Indeed, mutations in cancer cells that cause chromosome instability (CIN) are now widely recognized to be an important driver in cancer initiation and progression. These CIN mutations also represent tumour specific genetic vulnerabilities that could be exploited in developing new cancer treatments. Because the same building blocks are used to construct organisms as diverse as yeast, worms, and humans, "model organisms" provide powerful experimental tools for investigating the mechanistic basis of disease and for developing potential therapeutic interventions. The goals of our work are to understand the mechanisms of chromosome transmission at the levels of genes, pathways, and networks using yeast and the nematode worm as models, and to directly relate our studies to cancer and the development of new cancer therapies. Using yeast genetic techniques, in particular, global synthetic lethality analysis, we will identify yeast genes, and the corresponding human gene counterparts, that define potential therapeutic targets for selective killing of cancer cells relative to normal cells. We will use yeast to rapidly test millions of possible combinations of tumour-associated defects, drug targets, and chemotherapeutic agents to identify effective combinations, and will prioritize them for further testing in tumour cell cultures. The results of our proposed research will provide a basic understanding of the mechanisms of normal chromosome transmission, and of the corresponding defects associated with cancer pathology. Our results will also lead to the identification of new drug targets and will enable the identification of new small molecule inhibitors and combination therapies that could be used for the selective killing of cancer cells in patients.