The oncometabolite 2-hydroxyglutarate (2-HG) is a signature biomarker in various cancers, where it accumulates as a result of mutations in isocitrate dehydrogenase (IDH). The metabolic source of 2-HG, in a wide variety of cancers, dictates both its generation and also potential therapeutic strategies, but this remains difficult to accessin vivo. Here, utilizing patient-derived chondrosarcoma cells harboring endogenous mutations in IDH1 and IDH2, we report that 2-HG can be rapidly generated from glutaminein vitro. Then, using hyperpolarized magnetic resonance imaging (HP-MRI), we demonstrate thatin vivoHP [1-13C] glutamine can be used to non-invasively measure glutamine-derived HP 2-HG production. This can be readily modulated utilizing a selective IDH1 inhibitor, opening the door to targeting glutamine-derived 2-HG therapeutically. Rapid rates of HP 2-HG generationin vivofurther demonstrate that, in a context-dependent manner, glutamine can be a primary carbon source for 2-HG production in mutant IDH tumors.

中文翻译：

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在IDH1 / 2突变肿瘤中谷氨酰胺代谢为Oncometabolite 2-羟基戊二酸酯的体内成像。

竞争性代谢物2-羟基戊二酸（2-HG）是各种癌症中的标志性生物标志物，由于异柠檬酸脱氢酶（IDH）的突变而积累。2-HG在多种癌症中的代谢来源决定了其产生以及潜在的治疗策略，但这在体内仍然很难获得。在这里，我们利用患者来源的软骨肉瘤细胞在IDH1和IDH2中具有内源性突变，我们报道了2-HG可在体外由谷氨酰胺快速生成。然后，使用超极化磁共振成像（HP-MRI），我们证明了体内HP [1-13C]谷氨酰胺可用于非侵入性地测量谷氨酰胺衍生的HP 2-HG的产生。这可以使用选择性IDH1抑制剂轻松调节，从而为靶向治疗谷氨酰胺衍生的2-HG打开大门。