Grant: Fellowship: Jean-François St-Denis (Prize)

Lung cancer is a devastating disease suffering from the lack of effective chemotherapeutic strategies. Recently, our laboratory has screened a panel of 189,290 diverse chemical compounds in search of new agents to treat lung tumours. This analysis revealed four drug candidates that were able to inhibit the growth of lung cancer cells without toxicity to healthy, normal lung cells. However, the processes by which the compounds carry out their effects remain unknown. The focus of this proposal is to identify the specific gene products targeted by these compounds in order to understand their mechanisms of action. First, I outline a novel strategy for the robust and accurate identification of drug targets which uses the compounds as "baits" to "fish" out binding proteins from cancer cells. Second, by programming cancer cells sensitive to the drugs to overproduce the identified targets, I aim to rescue these cells from the inhibitory effects, confirming the role of the proteins in mediating drug response. Third, by analyzing changes in the levels of other genes in response to drug treatment, I will be able to further characterize the cellular pathways in which the drug targets are involved and clarify their potential role in lung tumour development. Lastly, I will look for mutations in the targets, as well as other genes, in an attempt to uncover the features that make tumours vulnerable to drug treatment. Together, this work will lead to a better understanding of the molecular mechanisms underlying the properties of these novel anti-lung cancer compounds. Not only will this be essential in order to further develop these drugs for clinical use, it will ultimately lead to the discovery of other process that lung cancer cells remain dependant on for sustained growth that may be further exploited for therapeutic means.