ABSTRACT Gliomas remain among the most intractable problems in oncology. These tumors can be differentiated into 2 distinct subsets based on genetic profile. Those harboring mutations in Isocitrate Dehydrogenase 1 or 2 (IDH1/2) tend to occur in younger patients and follow a progression from slow growing, indolent tumors (low-‐grade), to rapidly proliferating high-‐grade tumors. The IDH gain-‐of-‐function mutations catalyze the reduction of α-‐ketoglutarate (αKG) to 2-‐ hydroxyglutarate (2HG), an oncometabolite that accumulates in millimolar concentrations in the tumor cell. 2HG has been shown to drive the malignant phenotype in a wide variety of cancers that harbor IDH1/2 mutations. The presence of these mutations in the earliest grade of glioma suggests that dependence on IDH may be during the indolent phase, prior to transformation to higher grade, which is characterized by an accrual of multiple tumor suppressor and oncogenic mutations that are powerful drivers of tumor proliferation. Adding support to this idea, we have demonstrated that despite low proliferative rates, the low-‐grade gliomas are highly metabolically active. We used 13C-‐ NMR in vivo in patients with IDH-‐mutated gliomas to determine the activity of metabolic pathways in low-‐ and high-‐ grade disease. Across the spectrum, we observed robust labeling of citric acid cycle intermediates and the 2HG pool from both substrates, a finding that is particularly striking for the low-‐grade gliomas and suggests that the metabolic state is independent of the proliferative state. Emerging phase 1 glioma clinical trial data from treatment with the selective IDH1 inhibitor, AG-‐120 (Agios Pharmaceuticals), shows that treatment of progressive low-‐grade gliomas, before radiographic progression to high-‐grade disease, is associated with prolonged stable disease. This is in marked contrast with rapid progression in patients with recurrent high-‐grade gliomas treated with the inhibitor. The question remains as to what the mechanism of stable disease is in the low-‐grade subgroup and whether treatment at an even earlier stage (prior to progression in the stable phase) is the optimal time for achieving a response. We hypothesize that low-‐grade gliomas, during the long period of stable disease prior to further transformation, are highly metabolically active with multiple substrates contributing to the dynamic regulation of the 2HG pool and in this state are dependent on sustained production of 2HG. Furthermore, we hypothesize that following progression to high-‐grade disease sustained production of 2HG is no longer essential to tumor growth. To test these hypotheses, we have 3 Specifi...