Ceramide-Directed Therapeutics for Treatment of AML

About This Grant

PROJECT SUMMARY Through three inter-related and inter-dependent Projects and four essential Cores, our team will define the biological basis of dysfunctional sphingolipid metabolism in AML and, in that process, validate new therapeutic targets for pharmacological treatment approaches. The premise of this P01 application is that targeting enzymes/factors responsible for dysfunctional sphingolipid metabolism & altered ceramide (Cer) resistance pathways will enable novel clinical options in AML. This is based on preliminary data indicating selective inhibitors of Cer detoxification can modulate specific “pools” of this bioactive lipid, which will interrupt pro-survival sphingolipid-signaling, block mitochondrial remodeling, and collapse AML metabolism to drive multiple cell death pathways. The overarching hypothesis to be tested by all Projects is that increasing intracellular pro-death Cer species, while simultaneously diminishing pro-survival phosphorylated (ceramide-1-phosphate (C1P) or sphingosine-1-phosphate (S1P)) or other Cer metabolites (glucosylCers or sphingomyelin), will yield efficacious treatments for AML. A common scientific theme of all Projects is the mechanistic investigation of drug resistance and cell death pathways, which can be directly altered with sphingolipid-based therapeutics. Major innovations of our P01 include the utilization of a bioinformatic and systems biology approach to integrate genomics, sphingolipidomics, and proteomics data from molecularly defined patient samples to reveal susceptible populations for testing combinatorial sphingolipid-targeted therapeutics in state-of-the-art patient- derived xenografts and genetically engineered murine models. The major goal of this proposal is to develop new sphingolipid-targeted therapeutics and sphingolipid-based classification schemes to improve clinical outcomes in AML. To achieve this goal, we have assembled an interdisciplinary team that includes recognized leaders in the fields of leukemia, nanotechnology, cell death, mitochondrial bioenergetics, and sphingolipids from the University (Univ) of Virginia, Penn State Cancer Institute, Wake Forest Cancer Center, Univ of Arizona, Univ of Alaska-Southeast, and Memorial Sloan-Kettering Cancer Center. We will be accomplished our goal through the following overarching five Specific Aims (SA) shared by all Projects and Cores: SA1: Evaluate the efficacy of therapeutics that elevate intracellular levels of pro-death Cer species in mechanism-based AML cell models & preclinical models. SA2: Obtain preclinical pharmacokinetics, biodistribution, & toxicology data to support and/or expand applications for the FDA's Investigational New Drug (IND) program for SL-based AML therapeutics. SA3: Define the biochemical, metabolic, & molecular mechanisms underlying the synergies obtained with agents that target Cer detoxification pathways and mitochondrial remodeling systems. SA4: Understand the basis for dysfunctional SL metabolism in different molecularly & biochemically defined AML subtypes recently established by our group (i.e., SMhigh vs SMlow). SA5: Define & validate lipid-based biomarkers as diagnostic/prognostic indicators via OMIC-driven processes for precision-based treatments.