498O INDIGO: A randomized, double-blinded, phase III study of vorasidenib versus placebo in IDH1 or IDH2 low-grade glioma
Deborah T. BlumenthalIngo K. MellinghoffMartin J. van den BentMehdi TouatKatherine B. PetersJennifer ClarkeJoe MendezLiam WelshWarren MasonAndreas F. HottingerJuan Manuel Sepúlveda-SánchezWolfgang WickRiccardo SoffiettiArthur TronDongdong ZhaoShuchi S. PandyaLinda S. SteelmanIslam HassanPatrick Y. WenTimothy F. Cloughesy
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A recent cancer genome-sequencing project revealed that that novel point mutations in isocitrate dehydrogenase 1(IDH1) in the majority of gliomas at WHO Grade Ⅱ and Ⅲ and secondary glioblastomas at grade IV.IDH1 mutations are early events in the development of gliomas,and are related with prolonged survival in gliomas at various grades.Mutated IDH1 shows an altered catalytic activity that results in the elevated levels of α-ketoglutarate and 2-hydroxyglutarate.The correlations among the gliomas pathological diagnosis,tumor genesis,the therapeutic potential for targeting mutant IDH enzymes are discussed in this review.
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Gliomas are primary tumors of the human central nervous system with unknown mechanisms of progression. Isocitrate dehydrogenase-1 (IDH1) mutation is frequent in diffuse gliomas such as oligodendrogliomas. To gain insights into the physiopathology of oligodendrogliomas that have a better prognosis than other diffuse gliomas, we combined microdissection, 2-D DIGE and MS/MS focusing on proteome alterations associated with IDH1 mutation. We first compared tumor tissues (TT) and minimally infiltrated parenchymal tissues (MIT) of four IDH1-mutated oligodendrogliomas to verify whether proteins specific to oligodendroglioma tumor cells could be identified from one patient to another. This study resulted in identification of 68 differentially expressed proteins, with functions related to growth of tumor cells in a nervous parenchyma. We then looked for proteins distinctly expressed in TT harboring either mutant (oligodendrogliomas, n=4) or wild-type IDH1 (oligodendroglial component of malignant glio-neuronal tumors, n=4). This second analysis resulted in identification of distinct proteome patterns composed of 42 proteins. Oligodendrogliomas with a mutant IDH1 had noteworthy enhanced expression of enzymes controlling aerobic glycolysis and detoxification, and anti-apoptosis proteins. In addition, the mutant IDH1 migrated differently from the wild-type IDH1 form. Comparative proteomic analysis might thus be suitable to identify proteome alterations associated with a well-defined mutation.
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Glioma is the most common intracranial malignant tumor, with poor prognosis. The new World Health Organization (WHO) integrated classification (2016) for diffuse glioma is mainly based on the status of the isocitrate dehydrogenase (IDH) gene ( IDH ) mutation and 1p/19q codeletion, with diffuse glioma separated into three distinct molecular categories: chromosome 1p/19q codeletion/ IDH mutant, 1p/19q intact / IDH mutant, and IDH wild‐type. Gliomas harboring 1p/19q codeletion but without IDH mutation are rare and cannot be classified according to the new revision of the WHO classification. Here we report three high‐grade gliomas with this atypical molecular phenotype, and describe their histological and immunohistochemical features, the status of mutations in TERT promopter, H3F3A, HIST1H3B , and BRAF , as well as MGMT promoter methylation, and prognosis. Considering morphology, molecular parameters, and patients prognosis, we found that high‐grade gliomas harboring 1p/19q codeletion but without IDH mutation were not typical glioblastoma multiforme (GBM) but were more likely to be GBM than anaplastic oligodendroglioma.
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Isocitrate dehydrogenase 1 (IDH1) mutations have been discovered to be frequent and highly conserved in secondary glioblastoma multiforme and lower-grade gliomas. Although IDH1 mutations confer a unique genotype that has been associated with a favorable prognosis, the role of the mutated IDH1 enzyme and its metabolites in tumor initiation and maintenance remains unresolved. However, given that IDH1 mutations are homogeneously expressed and are limited solely to tumor tissue, targeting this mutation could potentially yield novel treatment strategies for patients with glioblastoma multiforme.
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Purpose of review Isocitrate dehydrogenases, IDH1 and IDH2, decarboxylate isocitrate to α-ketoglutarate (α-KG) and reduce NADP to NADPH. Point mutations of IDH1 and IDH2 have been discovered in gliomas. IDH mutations cause loss of native enzymatic activities and confer novel activity of converting α-KG to 2-hydroxyglutarate (2-HG). The mechanisms of IDH mutations in gliomagenesis, and their value as diagnostic, prognostic marker and therapeutic target have been extensively studied. This review is to summarize the findings of these studies. Recent findings Crystal structural studies revealed conformation changes in mutant IDHs, which may explain the gain of function by mutant IDHs. The product of mutant IDHs, 2-HG, is an inhibitor of α-KG-dependent dioxygenases, which may cause genome-wide epigenetic changes in human gliomas. IDH mutations are a favorable prognostic factor for human glioma and can be used as biomarker for differential diagnosis and subclassification rather than predictor of response to treatment. Preliminary data suggested that inhibiting production of the substrate of mutant IDH enzymes caused slow-down of glioma cell growth. Summary As valuable diagnostic and prognostic markers of human gliomas, there is still a lack of knowledge on biological functions of mutant IDHs, making targeting IDHs in glioma both difficult and unsecured.
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Mutations in isocitrate dehydrogenase (IDH), a key enzyme in the tricarboxylic acid cycle, have recently been found in ~75% glioma and ~20% acute myeloid leukemia. Different from the wild-type enzyme, mutant IDH1 catalyzes the reduction of α-ketoglutaric acid to D-2-hydroxyglutaric acid. Strong evidence has shown mutant IDH1 represents a novel target for this type of cancer. We found two 1-hydroxypyridin-2-one compounds that are potent inhibitors of R132H and R132C IDH1 mutants with Ki values as low as 120 nM. These compounds exhibit >60-fold selectivity against wild-type IDH1 and can inhibit the production of D-2-hydroxyglutaric acid in IDH1 mutated cells, representing novel chemical probes for cancer biology studies. We also report the first inhibitor-bound crystal structures of IDH1(R132H), showing these inhibitors have H-bond, electrostatic and hydrophobic interactions with the mutant enzyme. Comparison with the substrate-bound IDH1 structures revealed the structural basis for the high enzyme selectivity of these compounds.
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