Ceramide-Directed Therapeutics for Treatment of AML
openNCI - National Cancer Institute
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.
Up to $2.7M
health research