Grant: Operating Grant

Lung cancer is the leading cause of cancer death in globally and in Canada, killing more people than breast, prostate and colorectal cancers combined. Unfortunately, for the majority of Canadians diagnosed with non-small cell lung cancer (NSCLCs) today, the prognosis remains the same as it did twenty years ago, less than a 5% five year survival rate. While standard chemotherapies have failed, there is hope. A coalescence of human genetic and biochemical data have identified a number of "cancer genes" that may be good 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 vast majority of NSCLC patients. RAS and BRAF genes are the most prevalent mutated oncogenes in many human cancers, particularly in NSCLCs (>25%), yet available data suggest these mutant oncogenes do not act on their own: they require additional cooperating genes for cancer genesis and progression. This proposal aims to uncover what these cooperating genes are, how they work at molecular level, and when they are important in the evolution of a fully malignant metastatic cell - all of which are paramount to discovering new and effective cancer treatments. Genetically modified mouse models (GEMMs) 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, the timing and the genetics of tumour initiation. 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.