From Standard Treatment to Personalized Medicine: Role of IDH1 Mutations in Low-Grade Glioma Evolution and Treatment
Article Outline
For glioma patients today, therapy is chosen and implemented essentially on histopathological bases. Currently, an individual patient's biologic data is rarely used in a systematic way to guide and predict the best course of therapy (2). The advent of low-cost, individual genomic and proteomic analysis provides hope that we are entering a new era of personalized, patient-specific care. As far as glioma evolution and therapy are concerned, a new study by Dang et al. published in Nature in December 2009 (1) focused on the role of mutated NAPD+-dependent isocitrate dehydrogenase enzyme (IDH) genes as possible oncogenes (Figure 1). The possibility that tumor cells may develop typical metabolic profiles contributing to tumorigenesis is not a new concept (6). IDH in astrocytes is involved in the conversion of isocitrate to α-ketoglutarate both in the mitochondria as part of the Krebs cycle (IDH2, IDH3) and in the cytoplasm (IDH1), resulting in production of NADPH as a source of energy for cell metabolism. Mutations of IDH1 had been demonstrated in approximately 80% of Grade II and III gliomas and secondary glioblastomas (GBMs) (7, 8). In GBMs and anaplastic astrocytomas, the presence of the mutated fenotype was associated with a better prognosis (8). The mutations that had been studied occurred at a single amino acid residue of IDH1, arginine 132, which was most commonly mutated to histidine (R132H) (7, 8). When considering other possible mutations that had been implicated in the tumorigenesis of brain tumors, it seemed that IDH1 was often the first one to occur (7). Therefore, it had been postulated that IDH1 mutations were selected for early tumorigenesis. More recently, data had been provided showing a reduced conversion of isocitrate to α-ketoglutarate by the mutated IDH1 isoform as compared to wild type. How this reduced activity could lead to early damages and tumorigenesis was still unclear. One of the hypotheses implicated that in IDH mutated cells, because of the low levels of α-ketoglutarate that acts as a cofactor together with oxygen, the activity of proline hydroxylases was reduced. This enzyme is involved in the catabolism of hypoxia-inducible factor 1 (HIF1), involved in tumor angiogenesis. The loss of inhibition ensured by proline hydroxylases could increase HIF1 levels and related angiogenesis, as already demonstrated in nonglial cancer (4). The fact that only the single codon of arginine 132 had to be mutated in glial cells to promote malignant transformation was suggestive of a mechanism different from simple enzyme inactivation and decreased α-ketoglutarate production.
Figure 1.
Tumorigenic methabolic pathways in IDH1 mutated glial cells (reprinted and adapted from Cancer Cell [3] with permission from Elsevier). Isoforms of Krebs cycle enzymes (light blue) operate in the mitochondrion and the cytosol. The two major carbon sources for energy production are glucose and glutamine, which are catabolized via glycolysis (green) and glutaminolysis (purple), respectively. Dang et al. (1) proposed a new gain-of-function role for glioma-associated mutants of IDH1. R132 mutations of IDH1 generate a new enzyme that produces 2-hydroxyglutarate from α-ketoglutarate, and increased 2-hydroxyglutarate strongly correlates with cancer formation. The tumorigenic mechanism is not yet understood, but some possibilities involve activations of reactive oxygen species or inhibition of proline-hydroxylases, the last increasing hypoxia-inducible factor transcription.
Dang et al. (1) explored the hypotheses that IDH1 mutations may influence the enzyme's ability to act on α-ketoglutarate. First of all, they analyzed the metabolic profiles of U87 and LN-18 glioblastoma cells transfected with R132H mutated IDH1: No differences between mutated and wild type cells were found in the amount of metabolites involved in Krebs cycle, including α-ketoglutarate; on the contrary, an increase in 2-hydroxyglutarate (2-HG) was found in cell extracts and in the medium of glioma cells bearing the IDH1 mutation. The authors elegantly demonstrated that, in addition to impaired oxidative decarboxylation of isocitrate, all different forms of IDH1 mutations found in human glioma cells provide the ability to catalyze direct NADPH-dependent reduction of α-ketoglutarate to 2-HG. A similar significant increase in 2-HG levels was then measured directly on human IDH1 mutated glioma samples, thus further confirming in vitro findings. Finally, X-ray analyses of the mutated enzyme revealed that mutation at arginine 132 caused a different conformation of the active site, which could change affinity for the substrate.
These data open a new perspective on the oncogenic mechanism of IDH1 mutation in gliomas. The authors give different explanations. Regardless of the mechanisms, it seems likely that the gain-of-function ability of cells to produce 2HG as a result of R132 mutations in IDH1 contributes to tumorigenesis. We have previously proposed that patients suffering with 2-hydroxyglutaric aciduria, a condition associated with the presence of high levels of 2-HG in brain and other organs, are at a high risk of developing brain tumors (5). In addition, elevated brain levels of 2HG could result in increased ROS levels that, associated with alterations in NADPH metabolism, could contribute to an increased risk of cancer. 2HG may also be toxic to cells by competitively inhibiting enzymes involved in glial cell metabolism, such as transaminases, which allow use of glutamate nitrogen for amino and nucleic acid biosynthesis, and α-ketoglutarate-dependent proline-hydroxylases, such as those that regulate Hif1α levels. The apparent codominance of the activity of mutant and wild-type IDH1 is consistent with the possibility that wild-type IDH1 could directly provide NADPH and α-ketoglutarate to the mutant enzyme.
These findings may have relevant clinical implications. First, the mutation of IDH1 and possibly detection of increased levels of 2-HG could be used to identify patients with glioblastoma with a better prognosis. In addition, patients with lower-grade gliomas may potentially benefit by the therapeutic inhibition of 2HG production, in terms of slowing or halting conversion of lower-grade glioma into lethal secondary glioblastoma, changing the course of the disease. However, a number of questions remain unanswered. From a clinical point of view, low-grade gliomas are mostly diagnosed when they are already symptomatic and with a sizable tumor mass. This implies that a number of different intracellular pathways have been activated after the initial mutation. Even if the hypothesis that IDH1 mutation is the first hit in glioma tumorigenesis, leading to 2-HG overproduction, will be confirmed in future studies, we cannot infer that pharmacological inhibition of 2-HG would be sufficient to inhibit glioma evolution to glioblastoma. Despite these limitations, this important study invites neurosurgeons to switch their minds from standardized protocols and surgeries toward customized and biomolecular-guided treatments.
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PII: S1878-8750(10)00086-0
doi:10.1016/j.wneu.2010.02.050
© 2010 Elsevier Inc. All rights reserved.
