Glioblastoma (GBM) continues to be an invariably fatal malignancy. The established approach for understanding the biology of these aggressive tumors in an effort to identify novel molecular targets has largely been genotype based. Unfortunately, clinical gains offered by this level of understanding have been limited, largely based on the complex nature of signaling networks associated with tumorigenesis and the inability to delineate the key functional signaling pathways actually driving growth in an individual tumor. While cancers have access to a wide variety of genetic and/or epigenetic modifications, there are a limited number of metabolic strategies that they can employ. The underlying hypotheses of our research are that (1) activation of specific metabolic programs are required during glioma tumorigenesis, and (2) these pathways are targetable. We recently performed global metabolomic profiling in ~70 gliomas with liquid and gas chromatography (LC/GC) coupled with tandem mass-spectrometry (MS) using a metabolomic library consisting of >2000 standards in an effort to identify unique metabolic programs utilized by GBM. A key discovery was the identification of the accumulation of the metabolic intermediate cysteine sulfinic acid (CSA) in GBM, which ranked as the metabolite with the highest relative accumulation when compared to Grade II glioma. This represents the first identification of this metabolite in the context of cancer biology. We went on to optimize assays to quantify CSA levels in tissue, confirmed activation of this metabolic signaling axis in both patient derived tumors and GBM cell lines, and established its role in adapting to hypoxia. In the proposed study, we now seek to validate this metabolic node using flux-based studies and determine its potential to serve as a novel molecular target in GBM.

Public Health Relevance

The established approach for both understanding and treating cancer has largely been genotype based. Unfortunately, clinical gains offered by this level of understanding have been limited, largely based on the complex nature of signaling networks associated with tumorigenesis and the inability to delineate the key 'functional' signaling pathways actually driving growth in an individual tumor. While cancers have access to a wide variety of genetic and/or epigenetic modifications, there are a limited number of metabolic strategies that they can employ. We recently identified a novel metabolic pathway unique to a brain tumor termed glioblastoma (GBM) that appears to play a role in its aggressive phenotype. In the proposed study, we now seek to understand its biologic consequence and evaluate its potential to serve as a novel molecular target in GBM. If successful, these findings will provide the framework for the development of novel, metabolism-based therapeutic interventions targeting the aggressive phenotype of GBM.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS090087-01A1
Application #
9111392
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Fountain, Jane W
Project Start
2016-05-01
Project End
2018-04-30
Budget Start
2016-05-01
Budget End
2017-04-30
Support Year
1
Fiscal Year
2016
Total Cost
Indirect Cost
Name
William Beaumont Hospital
Department
Type
DUNS #
076362110
City
Royal Oak
State
MI
Country
United States
Zip Code
48073
Ippolito, Joseph E; Yim, Aldrin Kay-Yuen; Luo, Jingqin et al. (2017) Sexual dimorphism in glioma glycolysis underlies sex differences in survival. JCI Insight 2: