Grant: Team Grant: Terry Fox New Frontiers Program in Cancer

Acute leukemias remain one of the most devastating and costly cancers with less than 1 in 5 adult patients surviving 10 years and some childhood patients failing current treatments. Research into how normal blood cells are formed and perturbations in leukemia have provided major insights into why cures are so hard to achieve, with many seminal contributions provided by this longstanding Program Project. These indicate that most human leukemias are sustained by a rare subset of "leukemia stem cells" which are often resistant to currently used drugs. Cures thus require treatments that effectively target these leukemia stem cells, ideally with little toxicity for normal cells. This now seems possible with the advent of modern tools that can identify every change in every gene in cells, and that can also determine whether and why every gene is being expressed. In addition, vast libraries of naturally occurring and synthetic chemicals that can target specific molecules in cells are now available. Our group now brings powerful genetic engineering tools to enable human models of aggressive leukemia to be rapidly created in the lab so that mechanisms of treatment resistance and new drugs and biomarkers can be efficiently analyzed and tested directly and repeatedly in human cells that mimic, but do not rely on, patients' cells. This is the overall goal of this Program renewal and its new cohesive theme. Three projects will focus on examples of the worst types of leukemia known, develop human models of these and, in concert with 2 groups of world experts in the molecular analysis of cells, will use these models to search for common therapeutic targets. Success will be facilitated by a strong history of interaction between the applicants complemented by collaborating scientists outside the funded team, the participation of 2 clinician scientists, a close relationship with the Leukemia Tumour Group of the BCCA, and the involvement of an outstanding group of trainees.