# Targeting Ceramide Glycosylation in AML

> **NIH NIH P01** · UNIVERSITY OF VIRGINIA · 2020 · $286,641

## Abstract

PROJECT SUMMARY
The sphingolipid (SL) ceramide is a potent tumor suppressor that contributes to the promotion of apoptosis and
autophagy. Management of these responses in cancer cells is dependent on the dynamic balance between
ceramide and its metabolites, some of which can promote cell survival. Maintaining elevated levels of intracellular
ceramide is important for supporting its unique anticancer properties. Thus, from a strategic point, controlling the
metabolism of ceramide offers new opportunities for regulating cancer growth. The goal of this work is to assess
innovative steps to develop ceramide into an effective anticancer agent to treat acute myelogenous leukemia
(AML), the most common type of leukemia in adults, and to evaluate the role of SLs in chemotherapy resistance.
There is a critical need to develop more effective therapies for AML, especially in relapse patients. Although
many hypotheses have been proposed to explain therapeutic relapse, none have led to a complete
understanding of the molecular mechanisms of AML resistance, and there have been few treatment advances
in 40 years. Our premise is that upregulated glycosylation of ceramide is the major metabolic avenue
contributing to ceramide neutralization in cancer cells, and it is also strongly associated with the multidrug-
resistant phenotype in cancer. This project will focus on targeting ceramide glycosylation to enhance and propel
ceramide-driven AML cell death. Two innovative strategies will be employed to increase intracellular ceramide
levels: 1) use of a nanoliposomal, cell-permeable ceramide analog, C6-ceramide (CNL, ceramide
nanoliposome), and 2) employment of ceramide “generators”, drugs such as 4-HPR (fenretinide) or PSC833
(valspodar), that increase intracellular levels of natural long-chain ceramides. These strategies will be evaluated
separately, in combination, and in the presence of agents that inhibit ceramide glycosylation. We hypothesize
that taking steps to pharmacologically increase and maintain intracellular ceramide levels will enhance the overall
anticancer impact of ceramide-centric therapy. Further, given new findings on chemotherapy selection pressure
in AML, we hypothesize that aberrant SL metabolism plays a key role in drug resistance and that targeting SL
metabolism will potentially circumvent drug resistance. The following three Specific Aims will be pursued to
achieve our goal of employing ceramide and SL therapy in AML.
 1. Determine the effects of chemotherapy selection pressure on SL metabolism and the drug resistant
 phenotype in AML.
 2. Determine the effects of inhibitors of ceramide glycosylation on cytotoxicity and mechanism of action of
 CNL and ceramide-generating drugs.
 3. Assess the anticancer activity of ceramide-centric therapeutics in AML preclinical models. We predict
 that using adjuvants to block ceramide glycosylation will enhance ceramide-centric (CNL + ceramide
 “generators”) therapy in AML.

## Key facts

- **NIH application ID:** 9937369
- **Project number:** 2P01CA171983-06A1
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Myles C. Cabot
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $286,641
- **Award type:** 2
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9937369

## Citation

> US National Institutes of Health, RePORTER application 9937369, Targeting Ceramide Glycosylation in AML (2P01CA171983-06A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9937369. Licensed CC0.

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