Grant: Doctoral Award - Frederick Banting and Charles Best Canada Graduate Scholarships

Traditional chemotherapy targets cancer cells. A newer class of cancer treatments called 'antiangiogenic cancer therapy' seeks to restrict the development of a solid tumor's blood supply, effectively inhibiting a tumor's growth by suffocating it. Most antiangiogenic agents that have received FDA approval for cancer treatment inhibits the vascular endothelial growth factor (VEGF) pathway. Other than VEGF, another protein family that regulates blood vessel growth is the angiopoietin family, which includes Ang1 (a 'blood vessel stabilizer' that reduces vessel leakiness and keep vessels quiescent) and Ang2 (a 'blood vessel destabilizer' that renders vessels leaky and initiates new capillary growth). In recent years, preclinical and early clinical studies have started investigating the use of Ang2 inhibitors (anti-Ang2 agents) as antiangiogenic cancer therapeutic agents. While inhibitors of the VEGF and Ang2 pathways are designed to limit the angiogenesis-supported growth of tumors once tumor cells have seeded into body organs, another potential anti-cancer strategy is to target the metastatic process of advanced cancers - by preventing circulating tumor cells from escaping blood vessels and seeding into body tissues in the first place. Here we hypothesize that Ang1 mimetics (pro-Ang1 agents) - engineered peptides that recapitulate endogenous Ang1's ability to activate its endothelial receptor, Tie2, thereby inducing Ang1 effects - may serve as a new class of vascular-targeting cancer therapeutics with anti-metastatic capacity through their ability to stabilize host microvascular beds (e.g., reduced leakiness and down-regulation of endothelial cell surface adhesion proteins). With this project, we propose to investigate the potential anti-metastatic efficacy of Ang1 mimetics, either administered as single agents or in combination with established VEGF/Ang2 pathway-targeted antiangiogenic agents, using mouse models of advanced cancer and metastatic disease.