Grant: Project Grant

Cancer is the excessive division of cells in the body. To duplicate, cells must separate two identical sets of chromosomes during mitosis and divide correctly. This process requires the coordinated activities of several proteins that have been conserved between species during evolution. The Polo kinase protein (Plk1) is necessary for cell division by interacting with and modifying other proteins. Several types of cancer cells become addicted to elevated Polo activity. Thus, if Polo is inhibited partially, cancer cells die while healthy cells can still live and divide. Efforts have been deployed to obtain molecules capable of blocking the catalytic activity of Polo. Some of them are in clinical trials for the treatment of various cancers and have given promising results. However, the toxicity and side effects of these drugs limit their use. Our goal is to gain new knowledge of how Polo functions and how the cell responds to interference with Polo. This information will help design more effective and less toxic therapies targeting Polo in cancers. Recent findings by us and others have indicated the existence of previously unrecognized levels of regulation of Polo. The proposed research will build on these discoveries to uncover the precise molecular mechanisms controlling Polo activity in space and time during cell division so that it can fulfill its functions. For this part of the project, we will use the fruit fly Drosophila as a model system allowing a powerful combination of approaches. The new knowledge will provide basis to efforts in the development of compounds that interfere with specific aspects of Polo functions to kill cancer cells but not healthy cells. We will also use the new CRISPR technology to search for genes that become essential in the presence of low doses of Polo inhibitors in human cells. This information will direct the development of combinatorial therapies simultaneously targeting Polo and synergic mechanisms in cancer cells.