Biologic consequence and therapeuticimplications of cysteine catabolism in glioblastoma



 DESCRIPTION (provided by applicant): 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.