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

I am studying cancers that result when the protein segment called PNT, encoded by the ETV6 gene, becomes improperly fused to another gene fragment that encodes a protein tyrosine kinase (PTK). This phenomenon is called a chromosomal translocation, and the PNT-PTK chimera is an oncoprotein (a protein that leads to tumors). The specific PNT-PTK protein I am studying, called ETV6-NTRK3 (EN), has been implicated in a multitude of different cancers affecting many different demographics. These oncoproteins self-associate (bind to themselves) within our cells and cause unregulated stimulation of cellular signals. This in turn leads to aberrant cellular growth and ultimately cancers, such as congenital fibrosarcoma and secretory breast carcinoma. My goal is to find a compound that prevents this self-association, thus making the oncoprotein inactive and preventing unregulated cellular growth. I will use high-throughput screening tests to search extremely large chemical libraries for molecules that prevent this self-association. I will also test the binding of small compounds to the PNT domain to use as "building blocks" to design an inhibitor. I will characterize the effects of these candidate inhibitory molecules using techniques including nuclear magnetic resonance (NMR) spectroscopy and isothermal titration calorimetry (ITC), Initially, these inhibitors will help us understand the mechanisms of cellular transformation that occur in cancers arising from ETV6 chimeric oncoproteins such as EN. However, my long-term goal is to optimize the pharmacological properties of these inhibitors in animal models as a step towards developing new therapeutic against ETV6-related cancers.