Grant: Master's Award: Canada Graduate Research Scholarships - Master's program

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype characterized by rapid progression and metastatic spread to other parts of the body. Treatment with surgery, radiation, chemotherapy, immunotherapy and other drugs provides limited benefits for these patients, and many will die of progression to lethal metastatic disease. Thus, there is an urgent need to develop more effective treatments for patients with TNBC. Calpains are enzymes that promote TNBC metastasis, positioning them as promising novel therapeutic targets. Inhibiting Calpains with drugs that interfere with their enzymatic activity by binding in their active sites has been challenging due to their structural similarity to many other proteins whose unintended “off-target” inhibition would cause toxicity in patients. Proteolysis-targeting chimeras (PROTACs) are an exciting new type of drug that can circumvent this specificity and toxicity problem by binding away from the enzyme active site, where there is no similarity to other proteins. Their mechanism of action is promoting the destruction of their target, rather than just inhibiting their functions. However, it remains to be seen if PROTAC-mediated Calpain destruction can be sufficiently achieved in tumour-bearing animals to suppress TNBC metastasis. This project will engineer a PROTAC system designed to target Calpain in TNBC cells and then test it in cultured cancer cells. Once it has been optimized in cultured cells, tumours will be generated in mice to test the ability of the PROTAC to prevent metastatic spread of the cancer. This research will establish the feasibility of using PROTACs to inhibit TNBC metastasis and guide the development of novel therapeutic strategies for this aggressive cancer subtype.