Project 457141

Leukemia is the most common childhood cancer and the second greatest cause of pediatric cancer mortality in Canada. Chemotherapy directed to the central nervous system (CNS) is a critical part of treatment because leukemia that spreads there is often fatal. However, CNS-directed chemotherapy suffers from serious side effects including long-term cognitive disability. One way to reduce CNS toxicity and improve outcomes for survivors would be to create targeted therapies that exploit cancer-specific vulnerabilities, but few currently exist. A unique but understudied aspect of leukemia in the CNS is that cancer cells are moving from the blood to a new and quite distinct metabolic environment: the cerebrospinal fluid (CSF). CSF has significantly lower levels of essential nutrients such as sugars, proteins, and fatty acids as compared to the blood. I hypothesize that adapting to this new environment creates unique and targetable weaknesses in spreading leukemia cells. The central goals of this proposal are, therefore, to comprehensively characterize the metabolic environment of human CSF and the intrinsic adaptations that leukemia cells must undergo to survive there. Specifically, I will (1) apply an advanced method (mass-spectrometry) to measure the nutrients in the CSF of pediatric leukemia patients over the course of treatment, and (2) use comprehensive genetic tools to decipher what metabolic pathways are critical for the leukemia cells' survival in the CNS of mice. Nutrients we predict to be consumed by leukemia cells in (1) will inform the pathways we pursue genetically in (2). Further experiments using drugs targeting the genes or nutrients I find to be essential for leukemia cells in the CNS will verify whether these metabolic adaptations can be targeted therapeutically. This research may reveal novel, targetable vulnerabilities of leukemia in the CNS which could reduce the use of toxic chemotherapy.