Grant: Project Grant

Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in Canada, and although advances in treatment options have improved the overall survival for early stage CRCs, ~50% of individuals are still diagnosed with late stage disease that is often incurable. The development of highly specific, anti-cancer treatments is a significant research challenge; however, recent efforts suggest that exploiting the mutated genes and abnormal pathways that drive cancer development may hold tremendous clinical potential. Accordingly, greater insight into the mutated genes and abnormal pathways driving CRC formation is needed so that new treatment strategies and drug options can be developed that exploit them. Mutations in specific genes cause genome instability, which is an early step in the development of most CRCs. Genome instability often leads to abnormal numbers of chromosomes (structural elements that contain the DNA or genes) that further promote cancer development. We believe that to create new, effective chemotherapeutic options requires a deeper understanding of the abnormal genes and pathways driving CRC formation. In this regard, emerging data have identified a gene (USP22) that we suspect is a driver of CRC. Data from patient samples shows that USP22 is altered in ~50% of CRCs, while our pilot studies show that reduced expression causes genome instability and is associated with changes in chromosome numbers, which collectively suggest that abnormal expression may play a key role in CRC. To explore this possibility, we will employ newly generated and disease relevant models along with leading-edge genetic and cell biology techniques to gain unprecedented insight into USP22 and its role in CRC development. We will exploit this information to identify novel drug targets and lead chemotherapeutics that we will test in pre-clinical studies to ideally and ultimately deliver new therapeutic options to individuals diagnosed with CRC.