Sphingolipid Pathway as a Source of Vulnerability in IDH1(mut) Glioma

SIMPLE SUMMARY: The presence of the IDH mutation in glioma raises the possibility that these CNS malignancies could be targeted with metabolic-based therapeutics, however, the exploration of the role that regulatory lipids, such as sphingolipids serve within the IDH1(mut) gliomas remains limited. Our study aimed to identify vulnerabilities within the sphingolipid metabolism that could be exploited therapeutically. We revealed elevation in certain lipids produced along the sphingolipid pathway for IDH1 mutated glioma cells and upregulation of the corresponding enzymes. We demonstrated that inhibiting sphingosine kinase which exacerbating the imbalance between sphingosine and sphingosine 1-phosphate leads to cell death, specifically for IDH1(mut) gliomas. These findings present potential to translate into targets for the development of metabolic therapies that may promote improved prognosis for patients diagnosed with IDH1(mut) gliomas. ABSTRACT: In addition to providing integrity to cellular structure, the various classes of lipids participate in a multitude of functions including secondary messengers, receptor stimulation, lymphocyte trafficking, inflammation, angiogenesis, cell migration, proliferation, necrosis and apoptosis, thus highlighting the importance of understanding their role in the tumor phenotype. In the context of IDH1(mut) glioma, investigations focused on metabolic alterations involving lipidomics’ present potential to uncover novel vulnerabilities. Herein, a detailed lipidomic analysis of the sphingolipid metabolism was conducted in patient-derived IDH1(mut) glioma cell lines, as well as model systems, with the of identifying points of metabolic vulnerability. We probed the effect of decreasing D-2HG levels on the sphingolipid pathway, by treating these cell lines with an IDH1(mut) inhibitor, AGI5198. The results revealed that N,N-dimethylsphingosine (NDMS), sphingosine C17 and sphinganine C18 were significantly downregulated, while sphingosine-1-phosphate (S1P) was significantly upregulated in glioma cultures following suppression of IDH1(mut) activity. We exploited the pathway using a small-scale, rational drug screen and identified a combination that was lethal to IDH(mut) cells. Our work revealed that further addition of N,N-dimethylsphingosine in combination with sphingosine C17 triggered a dose-dependent biostatic and apoptotic response in a panel of IDH1(mut) glioma cell lines specifically, while it had little effect on the IDH(WT) cells probed here. To our knowledge, this is the first study that shows how altering the sphingolipid pathway in IDH1(mut) gliomas elucidates susceptibility that can arrest proliferation and initiate subsequent cellular death.