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Hominoid-specific enzyme GLUD2 promotes growth of IDH1R132H glioma.

ABSTRACT: Somatic mutation of isocitrate dehydrogenase 1 (IDH1) is now recognized as the most common initiating event for secondary glioblastoma, a brain tumor type arising with high frequency in the frontal lobe. A puzzling feature of IDH1 mutation is the selective manifestation of glioma as the only neoplasm frequently associated with early postzygotic occurrence of this genomic alteration. We report here that IDH1(R132H) exhibits a growth-inhibitory effect that is abrogated in the presence of glutamate dehydrogenase 2 (GLUD2), a hominoid-specific enzyme purportedly optimized to facilitate glutamate turnover in human forebrain. Using murine glioma progenitor cells, we demonstrate that IDH1(R132H) exerts a growth-inhibitory effect that is paralleled by deficiency in metabolic flux from glucose and glutamine to lipids. Examining human gliomas, we find that glutamate dehydrogenase 1 (GLUD1) and GLUD2 are overexpressed in IDH1-mutant tumors and that orthotopic growth of an IDH1-mutant glioma line is inhibited by knockdown of GLUD1/2. Strikingly, introduction of GLUD2 into murine glioma progenitor cells reverses deleterious effects of IDH1 mutation on metabolic flux and tumor growth. Further, we report that glutamate, a substrate of GLUD2 and a neurotransmitter abundant in mammalian neocortex, can support growth of glioma progenitor cells irrespective of IDH1 mutation status. These findings suggest that specialization of human neocortex for high glutamate neurotransmitter flux creates a metabolic niche conducive to growth of IDH1 mutant tumors.

SUBMITTER: Chen R

PROVIDER: S-EPMC4191757 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Hominoid-specific enzyme GLUD2 promotes growth of IDH1R132H glioma.

Chen Ruihuan R Nishimura Merry C MC Kharbanda Samir S Peale Frank F Deng Yuzhong Y Daemen Anneleen A Forrest William F WF Kwong Mandy M Hedehus Maj M Hatzivassiliou Georgia G Friedman Lori S LS Phillips Heidi S HS

Proceedings of the National Academy of Sciences of the United States of America 20140915 39

Somatic mutation of isocitrate dehydrogenase 1 (IDH1) is now recognized as the most common initiating event for secondary glioblastoma, a brain tumor type arising with high frequency in the frontal lobe. A puzzling feature of IDH1 mutation is the selective manifestation of glioma as the only neoplasm frequently associated with early postzygotic occurrence of this genomic alteration. We report here that IDH1(R132H) exhibits a growth-inhibitory effect that is abrogated in the presence of glutamate ...[more]

PMID: 25225364

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Project description:PURPOSE:Somatic mutations of the isocitrate dehydrogenase 1 (IDH1) gene, mostly substituting Arg132 with histidine, are associated with better patient survival, but glioma recurrence and progression are nearly inevitable, resulting in disproportionate morbidity and mortality. Our previous studies demonstrated that in contrast to hemizygous IDH1R132H (loss of wild-type allele), heterozygous IDH1R132H is intrinsically glioma suppressive but its suppression of three-dimensional (3D) growth is negated by extracellular glutamate and reducing equivalent. This study sought to understand the importance of 3D culture in IDH1R132H biology and the underlying mechanism of the glutamate effect. METHODS:RNA sequencing data of IDH1R132H-heterozygous and IDH1R132H-hemizygous glioma cells cultured under two-dimensional (2D) and 3D conditions were subjected to unsupervised hierarchal clustering and gene set enrichment analysis. IDH1R132H-heterozygous and IDH1R132H-hemizygous tumor growth were compared in subcutaneous and intracranial transplantations. Short-hairpin RNA against glutamate dehydrogenase 2 gene (GLUD2) expression was employed to determine the effects of glutamate and the mutant IDH1 inhibitor AGI-5198 on redox potential in IDH1R132H-heterozygous cells. RESULTS:In contrast to IDH1R132H-heterozygous cells, 3D-cultured but not 2D-cultured IDH1R132H-hemizygous cells were clustered with more malignant gliomas, possessed the glioblastoma mesenchymal signature, and exhibited aggressive tumor growth. Although both extracellular glutamate and AGI-5198 stimulated redox potential for 3D growth of IDH1R132H-heterozygous cells, GLUD2 expression was required for glutamate, but not AGI-5198, stimulation. CONCLUSION:3D culture is more relevant to IDH1R132H glioma biology. The importance of redox homeostasis in IDH1R132H glioma suggests that metabolic pathway(s) can be explored for therapeutic targeting, whereas IDH1R132H inhibitors may have counterproductive consequences in patient treatment.

Project description:Abstract Immunotherapeutic concepts for brain tumors have been hampered by lack of selective measures to target the CNS and lack of truly tumor-specific antigens. But the concept of an immune privileged CNS has to be questioned due to survey of the brain by specific T-cells, CNS autoimmunity and presence of lymphatics. As tumor-specific antigens, mutated antigens have come into focus for all tumor entities. Mutations in the gene for isocitrate dehydrogenase 1 frequently occur in diffuse gliomas, mostly astrocytomas, resulting in a point mutation (mostly IDH1R132H). IDH1R132H is an ideal tumor-specific antigen, because it is tumor-specific, homogenously expressed and considered a driving mutation in glioma. Preclinical studies have shown that mutation-specific Th cell responses spontaneously occur in patients with IDH1-mutated gliomas and that a peptide vaccine encoding IDH1R132H is therapeutic in a humanized mouse tumor model. Based on these data we have initiated a multicenter, first-in-man, phase I clinical vaccine trial, which is planned to enroll 39 patients with newly diagnosed malignant IDH1R132H+ astrocytomas at eight German sites: NOA-16 (NCT02454634). The vaccine is made of an IDH1R132H peptide emulsified in mineral oil and administered with topical imiquimod. Vaccination is implemented into primary standard therapy. Primary end points are safety and immunogenicity as measured by IDH1R132H-specific antibodies and T cell responses. As of March 2016, 13 patients have been enrolled in the trial; no severe adverse events have been reported. We report here on 3 patients treated with the vaccine on a compassionate use basis. No patient experienced a regime-limiting toxicity as defined in the trial protocol. Two patients received all 8 doses of the vaccine; both developed IDH1-specific antibody responses, which were mutation-specific early after vaccination. Of these, one patient developed a vaccination-induced mutation-specific cellular response. The second patient had a high baseline mutation-specific T cell response, which was temporarily boosted by the vaccine. IFN-? catch assays from PBMCs of this patient revealed a Th cell-mediated response. To identify and clone IDH1R132H-specific TCR(s) for adoptive T cell therapy, single T cells from this patient specifically responding to IDH1R132H were sorted and subjected to TCR sequencing. 11 TCRs have been identified so far and will be cloned and validated. In summary, we demonstrate for the first time the induction of a mutation-specific humoral and cellular immune response to the IDH1R132H neoepitope after peptide vaccination of patients with IDH1R132H-mutated gliomas. The ongoing trial will analyze safety and immunogenicity of the vaccine in a defined patient cohort, which also allows for collecting data on therapeutic efficacy.

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Hominoid-specific enzyme GLUD2 promotes growth of IDH1R132H glioma.

Publications

Hominoid-specific enzyme GLUD2 promotes growth of IDH1R132H glioma.

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