Grant: Project Grant

Lung cancer is the leading cause of cancer death globally and in Canada, where it kills more people than breast, prostate, colorectal and pancreatic cancers combined. Unfortunately for the majority of Canadians diagnosed with advanced non-small cell lung cancer (NSCLC) today, the prognosis remains the same as it did 20 years ago, a dismal 15% five-year survival. We clearly need better treatments. Recent human genetic and biochemical data have identified a number of "cancer genes" (oncogenes) that may be targets for future chemotherapeutic drugs. Indeed, several recent high-profile examples of new therapeutics have enjoyed success in the clinic -where it matters to the average Canadian. Despite these successes, these new therapies fail to provide clinical benefit for the most NSCLC patients. KRAS and BRAF genes are the most prevalent mutated oncogenes in many human cancers, particularly in NSCLCs. Yet the data suggest these mutant genes do not act on their own: they require additional cooperating genes for tumors progression malignancy. One such gene is the tumor suppressor P53, which is mutated in 70% of NSCLCs. This proposal aims to uncover how the tumor suppressor P53 works at molecular level and when it is important in the evolution of a fully malignant metastatic cell - both of which are paramount to discovering new and effective cancer treatments. Genetically modified mouse models (GEMM) are presently the gold standard for whole organism cancer modeling. We will make use of our novel GEMMs of human lung cancer where we can control the site, the number and the timing of specific genetic events. This enables us to query fundamental questions regarding the genetics of tumour initiation, progression, maintenance and ultimately, metastasis. Furthermore, these GEMMs of human lung cancer provide platforms for both the engineering and validation of targeted therapies with the goal of developing new therapies to alleviate suffering inflicted by this dreaded disease