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

Many types of cancers are caused when two unrelated pieces of DNA within the cell break and fuse back together creating a gene fusion. This research proposal focuses on a particular gene fusion called ETV6-NTRK3 (EN) that is responsible for different types of childhood tumors. Although these tumors can be treated, they often re-grow requiring multiple surgeries and chemotherapy. Chemotherapeutic drugs used today target all rapidly dividing cells, including normal healthy ones, and cause significant side effects in a growing child's body. Design of new drugs that specifically target cancer cells is therefore needed and will only be possible by understanding the molecular (gene and protein) events altered in the tumor cells. The EN gene fusion produces a fusion protein that contains a self-binding module called the ETV6 SAM domain. The EN SAM domain is fused to another module responsible for EN's activity called the NTRK3 protein tyrosine kinase (PTK) domain. EN fusion proteins bind each other through their SAM domains and polymerize resulting in the activation of their PTK domains. Activated EN polymers continuously send signals to the cell, telling it to divide, grow and resist cell death. A rational approach to targeting the tumor cells would be to eliminate the trigger for activation of uncontrolled cell growth. We believe that blocking the polymerization of the SAM domain is key to controlling ETV6 SAM domain fusion protein-mediated tumor progression. I will investigate the role of a protein modification called sumoylation in the SAM-mediated polymerization and subsequent tumor initiation/progression. Findings of this study will contribute significantly to the long-term goal of understanding the precise mechanism of tumor progression in cancers involving SAM domains, including several leukemias. This knowledge may be translated into clinical applications by helping in the design of new drugs that specifically destroy cancer cells while sparing normal ones.