Ceramide-directed therapeutics for treatment of AML

The University of Virginia received a $2.66 million Project Grant from the National Cancer Institute under the Cancer Treatment Research program (CFDA 93.395) awarded September 1, 2025, through August 31, 2030. The award supports a coordinated research initiative to develop ceramide-directed therapeutics for acute myeloid leukemia (AML) treatment. The program integrates three inter-related research projects and four essential core facilities to define the biological basis of dysfunctional sphingolipid metabolism in AML and validate new therapeutic targets. The research team will employ bioinformatic and systems biology approaches to integrate genomics, sphingolipidomics, and proteomics data from patient samples, identify susceptible populations, and test combinatorial sphingolipid-targeted therapeutics in patient-derived xenografts and genetically engineered murine models. The overarching goal is to develop novel sphingolipid-targeted therapeutic approaches and classification schemes to improve clinical outcomes in AML patients by selectively modulating ceramide and related lipid metabolite pools to interrupt pro-survival signaling and drive multiple cell death pathways.

The award encompasses five sub-awards to specialized research institutions providing essential research services and expertise. Sloan-Kettering Institute for Cancer Research (awarded November 24, 2025) provides Core B molecular analysis support including DNA and RNA extraction, cytokine assays, sequencing, and animal tissue coordination. The University of Arizona (awarded October 31, 2025) develops and optimizes therapeutic candidates for pharmacokinetic and pharmacodynamic studies. Jacksonville State University (awarded October 30, 2025) and Wake Forest University Health Sciences (awarded October 20, 2025) contribute specialized expertise in sphingolipid biology and mitochondrial bioenergetics. Pennsylvania State University's Hershey Medical Center (awarded October 10, 2025) maintains AML tissue banks, develops primary human AML stem cell cultures, and performs toxicity and pharmacokinetic studies while providing various animal models for therapeutic evaluation.

Abstract

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.