Project 458855

Metastatic cancer spread is the cause of poor prognosis in cancer. Canadian statistics show that patients with non-metastatic breast cancer have a 90% 3-year survival chance, but patients with metastatic breast cancer have only a 40% chance. Therefore, if we prevent the metastatic process, that will result in patients' better outcomes. Recent scientific reports show that human enzymes called calpain-1 and calpain-2 promote pro-tumorigenic and pro-metastatic properties of cancer. These enzymes are known to affect intracellular signals that can induce cancer cell motility and cancer cell survival. Moreover, high presence of calpain-1 and calpain-2 in the breast tumor has been shown to predict bad outcomes in several subtypes of breast cancer. Of particular interest is the triple negative breast cancer (TNBC) subtype, since it is often unresponsive to the existing therapies, so the unmet need for better therapeutics is more urgent for patients with that subtype of cancer. Before, I have shown that genetically disabling calpains in the TNBC tumor effectively halted its metastatic potential in a mouse model. Therefore, currently I hypothesize that disabling calpains with a pharmacological inhibitor instead will halt metastasis in a mouse model as well. My first aim in this project is to identify a molecule that can inhibit calpain by preventing the association of its subunits. I will accomplish this using my protein-protein interaction biosensors in a high-throughput robotic assay system. The second aim is to use the molecule identified in Aim 1, or its derivative, to reproduce the anti-metastatic features of a calpain-deficient cell by targeted inhibition in a cell system and in a mouse model of metastasis. Finally, I will identify other calpain-dependent cell functions that will make cancer cells more sensitive to chemotherapeutic agents. By the end of the project, I will have verified a calpain inhibitor that can be then tested in a clinical setting.