# Targeted Sphingolipid Metabolism for Treatment of AML

> **NIH NIH P01** · UNIVERSITY OF VIRGINIA · 2020 · $2,054,089

## Abstract

PROJECT SUMMARY
Through three inter-related and inter-dependent Projects and four essential Cores, our team will continue to
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 the renewal P01 application is
that targeting enzymes responsible for dysfunctional sphingolipid metabolism will lead to new clinical options in
AML. The overall hypothesis to be tested by all projects is that increasing endogenous pro-apoptotic ceramide
species, while diminishing pro-survival phosphorylated or glycosylated ceramide metabolites, will yield
efficacious treatments for AML. The overall premise of this renewal application are the exciting results from the
first-in-man clinical trial of ceramide nanoliposomes for solid tumors (NCT02834611), demonstrating the lack of
dose-limiting toxicities at doses where stable disease is observed. Exciting preliminary and published in vivo
data provide the rationale for nanoscale delivery vehicles for exogenous ceramide as an adjuvant therapy to
support standard of care therapy (low-dose AraC and venetoclax) in a phase Ib/IIa clinical trial for
relapsed/refractory AML (Project 1, CAV trial, UVA Protocol Review Committee approval #5414, pre-IND
142902). In addition, preliminary and published data are provided demonstrating that selective inhibitors of
ceramide metabolism (Projects 2-3) increase the clinical utility of agents that raise levels of pro-apoptotic
ceramides. A common scientific theme of all Projects is the mechanistic investigation of drug resistance and
programmed cell death, which can be directly altered with sphingolipid-based therapeutics. The major
innovation of our P01 is to utilize a bioinformatic and systems biology approach to integrate genomics,
sphingolipidomics, and proteomics data from molecularly defined patient samples to reveal susceptible
populations for testing innovative sphingolipid-targeted therapeutics in state-of-the-art patient-derived
xenografts, genetically engineered murine models, and most importantly, a clinical trial. The major goal of this
proposal is to develop new sphingolipid-targeted therapeutics for AML. The interdisciplinary team includes
leaders in the fields of leukemia (specifically AML), nanoscale delivery systems for bioactive lipids, programmed
cell death, and the biochemistry and biophysics of sphingolipids. This major goal will be accomplished through
the following overarching five Specific Aims that are shared by all Projects and Cores: 1) Evaluate the efficacy
of therapeutics that elevate exogenous or endogenous levels of pro-apoptotic ceramide species in animal and
clinical trials; 2) Obtain preclinical and clinical PK, bio-distribution, and toxicology data to support and/or expand
our FDA-IND for sphingolipid-based AML therapeutics; 3) Define the biochemical, biophysical, and molecular
mechanisms underlying the synergies obtained wit...

## Key facts

- **NIH application ID:** 9937366
- **Project number:** 2P01CA171983-06A1
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** MARK KESTER
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $2,054,089
- **Award type:** 2
- **Project period:** 2013-09-10 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9937366

## Citation

> US National Institutes of Health, RePORTER application 9937366, Targeted Sphingolipid Metabolism for Treatment of AML (2P01CA171983-06A1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9937366. Licensed CC0.

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