Metabolic Rewiring in Adult-Type Diffuse Gliomas

Abstract

Multiple metabolic pathways are utilized to maintain cellular homeostasis. Given the evidence that altered cell metabolism significantly contributes to glioma biology, the current research efforts aim to improve our understanding of metabolic rewiring between glioma's complex genotype and tissue context. In addition, extensive molecular profiling has revealed activated oncogenes and inactivated tumor suppressors that directly or indirectly impact the cellular metabolism that is associated with the pathogenesis of gliomas. The mutation status of isocitrate dehydrogenases (IDHs) is one of the most important prognostic factors in adult-type diffuse gliomas. This review presents an overview of the metabolic alterations in IDH-mutant gliomas and IDH-wildtype glioblastoma (GBM). A particular focus is placed on targeting metabolic vulnerabilities to identify new therapeutic strategies for glioma.

Keywords: glioma metabolism; isocitrate dehydrogenases (IDH); therapeutic strategies.

Figure 1

Glutamine metabolism supplies TCA cycle intermediates (anaplerosis). The cystine/glutamate antiporter xCT (SLC7A11) promotes extracellular cystine uptake for glutathione biosynthesis. α-KG, α-ketoglutarate; AsAT, aspartate aminotransferase; GDH, glutamate dehydrogenase; GLS, glutaminase; GSH, glutathione; ROS, reactive oxygen species.

Figure 2

The pathophysiological role of the IDH enzyme. As homodimers, IDH1 or IDH2 produce α-KG in the cytosol or mitochondria, respectively. The prevalence of the IDH mutation is high in adult-type low-grade gliomas. mIDH gains a neomorphic enzymatic activity, leading to 2-HG accumulation. Consequently, 2-HG competitively binds to ten-eleven translocation (TET) enzymes and histone lysine demethylase (KDMs). 2-HG, D-2-hydroxyglutarate; α-KG, α-ketoglutarate; G-CIMP, glioma-CpG island methylator phenotype; H3, KDM, histone lysine demethylase; mIDH1/2, mutant IDH1/2; TET, ten-eleven translocation protein.

Figure 3

Metabolic profiles of glioma characterized by plasma and the cerebrospinal fluid (CSF) of the patients, patient-derived cell lines, intracranial mouse models, and preclinical drug testing.