A recent genome wide analysis revealed that approximately 80% of grade II-III gliomas and secondary glioblasotomas harbor mutations in cytosolic isocitrate dehydrogenase 1 (IDH1). Subsequent studies revealed that the mutant IDH1 gained a new function, conversion of alpha- ketoglutarate to 2-hydroxyglutarate. Thus, alpha-ketoglutarate produced by wild-type IDH1 is consumed by the mutant IDH1, depleting cells of alpha-ketoglutarate. We hypothesized that cells with mutant IDH1 may be more susceptible to blockade of glutaminolysis, which plays a critical role in proliferation of tumor cells by serving as an alternative source of alpha-ketoglutarate. To test this hypothesis, the following aims will be pursued:
Aim 1.) Identify potent soluble GLS inhibitors with improved drug-like molecular properties;
Aim 2.) Assess antiproliferative effects of GLS inhibitors in D54 glioblastoma cell lines. Upon completion of this project, we expect to identify new GLS inhibitors with more drug-like molecular properties, which can serve as therapeutic prototypes to establish in vivo proof-of-concept in animal models of glioma in future.

Public Health Relevance

The goal of the proposed research is to conduct systematic SAR (structure-activity relationships) studies to identify kidney-type glutaminase (GLS) inhibitors as small molecule probes for evaluating the therapeutic utility of GLS inhibition in glioma with IDH (isocitrate dehydrogenase) mutations. New GLS inhibitors emerging from this project will be tested in comparative cell growth studies using D54 glioblastoma cell lines constitutively overexpressing either wild-type or mutant R132H IDH1. These studies should lead to the discovery of new GLS inhibitors with more drug-like properties, which can serve as therapeutic prototypes in future experiments to establish in vivo proof-of-concept in animal models of glioma.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS074151-02
Application #
8236925
Study Section
Special Emphasis Panel (ZRG1-MDCN-C (58))
Program Officer
Farkas, Rebecca M
Project Start
2011-04-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2014-03-31
Support Year
2
Fiscal Year
2012
Total Cost
$246,000
Indirect Cost
$96,000
Name
Johns Hopkins University
Department
Neurology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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