Gliomas are the most common primary malignant brain tumor in adults. Intermediate-grade gliomas (Grade II and III) and glioblastomas (GBM, grade IV) are essentially incurable due to their diffusely infiltrative nature. The vast majority of intermediate-grade gliomas and secondary GBMs harbor heterozygous missense mutations in the metabolic enzymes IDH1/2. IDH1R132H mutation confers a neomorphic enzyme activity that converts ?KG to D-(2)-hydroxyglutarate (D2HG). D2HG is thought to be an oncometabolite that alters epigenetics by inhibiting ?KG-dependent dioxygenases and creates a cellular state that is permissive to malignant transformation. IDH1/2 mutations also cause widespread metabolic reprogramming that alters the bioavailability of macromolecule precursors and disrupts normal biosynthetic pathways. Gliomas harboring IDH1/2 mutations must therefore adapt to altered metabolic flux by increasing the rate of glutaminolysis through glutaminase and glutamate dehydrogenase enzymes. Consistent with this view, it was recently reported that glutamate dehydrogenase 2 (GLUD2), a hominoid-specific enzyme that catalyzes conversion of l- glutamate to ?KG (a TCA metabolite and macromolecule precursor), increases the growth of IDH1R132H gliomas in an experimental brain tumor model. GLUD1/2 activity is important for anaplerotic glutaminolysis, a process that increases bioavailability of ?KG for biosynthetic pathways via the TCA cycle. This pathway provides macromolecule precursors for lipogenesis and nucleotide synthesis and promotes biomass expansion in tumor cells. Our preliminary studies demonstrate that GLUD2 is highly expressed in IDH1R132H tumors, GLUD2 increases growth of IDH1R132H neural stem cells (NSCs), and targeting GLUD1/2 in IDH1R132H- expressing glioma cells inhibits the progression of intracranial xenografts formed after transplantation in mice. We hypothesize that adaptively evolved properties of GLUD2 are critical for resolving IDH1R132H-induced metabolic liabilities in gliomas, and inhibiting GLUD2 will limit or stop the growth of these tumors. We will test this hypothesis by characterizing the mechanisms underlying the essential role of GLUD2 in NSC maintenance and glioma growth in the context of IDH1R132H mutation. Furthermore, we will use multiple preclinical murine models of IDH1R132H glioma to evaluate the therapeutic potential of GLUD2 inhibition for malignant gliomas. Results from these studies will reveal essential functions of GLUD2 in NSC biology, characterize novel metabolic sensitivities that can be exploited for drug therapy in IDH1 mutated gliomas, and validate a novel therapeutic target for a lethal disease.
Intermediate-grade gliomas and progressive high-grade gliomas harbor mutations in the metabolic enzymes IDH1/2, which cause widespread metabolic reprogramming in glioma cells. The proposed studies will investigate the potential for therapeutically targeting metabolic abnormalities in gliomas by inhibiting glutamate dehydrogenase 2 (GLUD2). Results from these studies will characterize a novel therapeutic target for a deadly form of malignant brain tumor.
| Waitkus, Matthew S; Diplas, Bill H; Yan, Hai (2018) Biological Role and Therapeutic Potential of IDH Mutations in Cancer. Cancer Cell 34:186-195 |
| Waitkus, Matthew S; Pirozzi, Christopher J; Moure, Casey J et al. (2018) Adaptive Evolution of the GDH2 Allosteric Domain Promotes Gliomagenesis by Resolving IDH1R132H-Induced Metabolic Liabilities. Cancer Res 78:36-50 |
