Douglas Benson

Introduction. Glioblastoma (GBM) is an aggressive malignant primary neoplasm of the central nervous system that is considered incurable using current treatment modalities¹. In recent years, efforts have been made to examine the process of oncogenesis in GBM, as well as identify specific mutations driving the malignant phenotype in order to improve therapy^2,3. Mutation of the citric acid cycle enzyme isocitrate dehydrogenase-1 (IDH1) and the resultant production of its novel metabolite 2-hydroxyglutarate (2-HG) have been identified to mediate key aspects of oncogenesis in subsets of these tumors^4-7, but also result in cellular metabolic alterations^8-10. Several studies have examined the effects of targeting these metabolic pathway changes with promising implications for future treatment approaches. The studies examined identified and focused on the effects NAD+ depletion¹¹ and glucose deprivation¹² in IDH1-mutated (mutIDH1) GBM. Methods. In the studies examined, various cell models for mutIDH1 glioma or glioblastoma were utilized. Metabolites in mutIDH1 GBM cells were quantified using LC-MS after treatment with IDH1 inhibitors. Naprt1 expression and methylation was measured in mutIDH1 versus wild-type. Relative in vitro cell viability of mutIDH1 GBM cells treated with two NAMPT inhibitors versus control were measured, and in vivo tumor growth studies using mutIDH1 GBM intracerebral mouse xenografts were performed using a NAMPT inhibitor. DARTS analysis was performed using ATP synthase and 2-HG. Cell viability was measured in mutIDH1 versus wtIDH1 cells in settings of glucose deprivation, including with ketones. Western blot for AMPK pathway proteins in these settings was performed. Results. mutIDH1 GBM cells showed alterations in the levels of TCA cycle intermediates, variations in NAD+ related to the suppression of Naprt1 mediated by mutIDH1/2-HG, and reduced viability or tumor growth in the setting of NAD+ depletion using NAMPT inhibitors¹¹. Through direct inhibition of ATP synthase by 2-HG, mutIDH1 glioblastoma cells exhibited drastically reduced cell viability in the setting of glucose deprivation, including in the presence of ketone bodies as an alternative respiration substrate¹². In both cases, these effects were associated with increased activation of the AMPK pathway^,12. Conclusion. Studies have found that IDH1 mutation and 2-HG accumulation alters the metabolism of glioblastoma cells, sensitizing them to NAD+ depletion and glucose deprivation due to Naprt1 pathway suppression and ATP-synthase inhibition, respectively. Metabolic disruption via these limitations activates the AMPK signaling pathway. Exploitation of these vulnerabilities using NAMPT inhibitors (for NAD+ depletion) or ketogenic diet (for glucose deprivation) represent potential novel avenues for treatment of a challenging disease.

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