Grant: CIHR Fellowship

Improved outcomes for breast cancer patients can be achieved through the development of novel targeted agents which act on key survival and proliferation pathways in cancer cells. This project explores calpain as a novel therapeutic target in breast cancer. Calpain is an intracellular calcium regulated protease, a protein that cleaves other proteins. Calpain mediated cleavage effectively regulates the cellular functions of its target proteins, including proliferation, survival and migration. We have shown that blocking calpain expression in breast cancer cells reduced their ability to grow tumors in mice. In addition, loss of calpain rendered cells either more or less susceptible to cell death depending on the specific toxic challenges. We hypothesize that these pro or anti-death functions relate to the different proteins calpain cleaves and their functions. Therefore, we need to identify relevant calpain targets. Using state-of-the-art technologies including large-scale proteome screens as well as preclinical cell and animal models, I will identify calpain targets and decipher the functional effects of calpain cleavage. Using this knowledge, I will predict how calpain inhibition can improve the therapeutic effects of established drugs designed to target specific proteins in the cancer cell. I will then test combinations of these targeted drugs with calpain inhibitors in animal tumor models. The ultimate goal will be the discovery of drug combinations that display additive or synergistic effects for the improvement of breast cancer treatment.