Acute myeloid leukemia (AML) is the most common form of acute leukemia and is increasing in incidence. While biological insight into the molecular pathogenesis of AML has greatly advanced, FDA-approved therapeutic strategies have changed little, with the 5-year survival rate remaining around 27%. This is largely attributed to the heterogeneous nature of AML; the variety of subtypes are defined by clinical, morphologic, cytogenetic, and molecular characteristics. Consequently, there is a need to develop more effective, molecularly-targeted therapies. Changes in the metabolome are the ultimate ?response? to a genetic modification, drug response, or disease process. Sphingolipids comprise a portion of the metabolome. Consequently, changes in the metabolome, including sphingolipids, can be more predictive of phenotype than other markers. The premise of our proposal is based on our published and unpublished studies that revealed perturbations of sphingolipid metabolism in AML and the efficacy of sphingolipid-based therapeutics for AML. The goals of this renewal are to extend these studies and further develop improved sphingolipid-based therapeutics. Towards this end, Core A is intended to serve as a scientific and methodological connection between the Projects to analyze changes in sphingolipid metabolism through mass spectrometry and qPCR- based analyses of cell line, preclinical, and patient samples. Furthermore, Core A will provide ADME/PK analyses to ascertain properties of sphingolipid-based therapeutics developed by the projects to facilitate drug development. These studies will expedite the design of safer and more effective strategies to address the current clinical need for improved therapeutics.

Public Health Relevance

Acute myelogenous leukemia (AML) is the most common acute form of leukemia affecting adults, and it lacks long-term efficacious therapies. Core A serves a vital role in hypothesis testing and generation for the projects by seeking to understand alterations in (glyco)sphingolipid metabolism in AML by providing standardized measurements of the sphingolipid pathways and ADME/PK analytical services to facilitate sphingolipid-based therapy development. The outcome of these studies will help define new therapeutic strategies for AML.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA171983-06A1
Application #
9937371
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2020-05-01
Budget End
2021-04-30
Support Year
6
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Virginia
Department
Type
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
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