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

Colorectal cancer (CC) is the 4th most common cause of cancer-associated death worldwide. Surgery, chemotherapy (CT), and radiotherapy (RT) are the most common treatments for CC. However, these treatments are rarely curative and cause severe side effects in patients. Moreover, 50% reoccurrence takes place due to therapeutic resistances particularly in this type of cancer. This is mostly due to the adaptation of cancer cells by acquiring resistance mechanisms against anti-cancer treatments. RT and CT used in CC commonly act by causing DNA damage leading to cancer cell death. However, cancer cells can survive by adapting the DNA damage through expression of DNA repair mechanism. The natural ability of cancer cells to repair DNA can undermine the clinical outcome of DNA damaging chemo and radiation treatments in CC. Inhibitors of DNA repair render tumors more susceptible to DNA damage by RT and CT, leading to higher rate of cancer cell death; but may act similarly on normal cells, leading to severe toxicity in patients. Our research team has identified a DNA-repair enzyme called polynucleotide kinase/phosphatase (PNKP), as a new target for drug development in CC. We have synthesized several effective small molecule inhibitors of PNKP that were shown to enhance the effect of RT and CT treatment in CC. Now, our focus is on the development of nanocarriers that can specifically deliver PNKP inhibitors to cancer cells while sparing normal cells. The nanocarriers of PNKP inhibitors are expected to enhance their anti-cancer effects in CC and at the same time reduce their side effects on normal cells. Through this approach, we expect to be one step closer to the development of more effective and less toxic new treatments for CC.