The goal of this project is to counteract the impact of the Warburg effect (i.e., abnormally high glucose utilization characteristic of cancer cells) on downstream glycosylation endpoints that contribute to oncogenic progression and drug resistance. The general approach of inhibiting glycolysis to therapeutically address the Warburg effect has received increasing interest in the past few years with most attempts focused on inhibiting the intake of glucose into a cell or subsequently, into energy processing pathways. By contrast, this project takes a different strategy that involves targeting enzymes found downstream of glycolysis in the hexosamine biosynthetic pathway. By inhibiting this pathway, levels of UDP-GlcNAc are lowered, which we predict will directly reduce two cancer-promoting biochemical mechanisms (specifically O-GlcNAc-modification of nucleocytosolic proteins and the cell surface galectin lattice) and indirect slow another (biosynthesis of building blocks for the production of cancer stem cell markers). Successful completion of these proof-of-principle experiments will provide a foundation for the animal and clinical translation of a new class of badly needed cancer drugs.

Public Health Relevance

Cancer continues to rank as a major killer of Americans, with close to one and a half million new cases each year and over half a million deaths. This proposal takes a new approach towards targeting aberrant glucose metabolism (an emerging 'hallmark of cancer') that contributes to metastasis and drug resistance and thereby thwarts a major driver of disease progression.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA191715-01
Application #
8813919
Study Section
Special Emphasis Panel (ZCA1-RPRB-O (O1))
Program Officer
Fu, Yali
Project Start
2014-12-03
Project End
2016-11-30
Budget Start
2014-12-03
Budget End
2015-11-30
Support Year
1
Fiscal Year
2015
Total Cost
$211,410
Indirect Cost
$80,910
Name
Johns Hopkins University
Department
Biomedical Engineering
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205