PROJECT SUMMARY Acute myeloid leukemia (AML) is the most common form of acute leukemia and is increasing in incidence. While biological insight into the molecular pathogenesis of AML has greatly advanced, FDA-approved therapeutic strategies have changed little, with the 5-year survival rate remaining around 27%. This is largely attributed to the heterogeneous nature of AML; the variety of subtypes are defined by clinical, morphologic, cytogenetic, and molecular characteristics. Consequently, there is a need to develop more effective, molecularly-targeted therapies. Changes in the metabolome are the ultimate “response” to a genetic modification, drug response, or disease process. Sphingolipids comprise a portion of the metabolome. Consequently, changes in the metabolome, including sphingolipids, can be more predictive of phenotype than other markers. The premise of our proposal is based on our published and unpublished studies that revealed perturbations of sphingolipid metabolism in AML and the efficacy of sphingolipid-based therapeutics for AML. The goals of this renewal are to extend these studies and further develop improved sphingolipid-based therapeutics. Towards this end, Core A is intended to serve as a scientific and methodological connection between the Projects to analyze changes in sphingolipid metabolism through mass spectrometry and qPCR- based analyses of cell line, preclinical, and patient samples. Furthermore, Core A will provide ADME/PK analyses to ascertain properties of sphingolipid-based therapeutics developed by the projects to facilitate drug development. These studies will expedite the design of safer and more effective strategies to address the current clinical need for improved therapeutics.