Non-invasive in vivo assessment of IDH1 mutational status in glioma
Non-invasive in vivo assessment of IDH1 mutational status in glioma
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DOI：
10.1038/ncomms3429
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发表时间：
2013-09-01
影响因子：
16.6
通讯作者：
Ronen, Sabrina M.
中科院分区：
文献类型：
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作者：
Chaumeil, Myriam M.;Larson, Peder E. Z.;Ronen, Sabrina M.
异柠檬酸脱氢酶1(IDH1)基因的功能获得突变在低级别胶质瘤和继发性胶质母细胞瘤中最为常见。它们导致肿瘤性代谢产物2-羟基戊二酸在细胞内积聚，是一种早期致病事件，被认为是治疗的靶点。在这项概念验证研究中，我们表明，[1-C-13]α-酮戊二酸可以作为代谢显像剂，用于非侵入性、实时、体内监测突变的IDH1活性，并可以告知IDH1的状态。利用C-13磁共振波谱结合溶解动态核极化，研究了超极化的[1-C-13]α-酮戊二酸在同基因胶质母细胞瘤细胞中的代谢命运。在表达野生型IDH1的裂解物和肿瘤中，只能检测到超极化的[1-C-13]α-酮戊二酸。相反，在表达突变IDH1的细胞中，也观察到超极化的[1-C-13]2-羟基戊二酸，无论是在细胞裂解产物中还是在原位肿瘤中都是如此。
Gain-of-function mutations of the isocitrate dehydrogenase 1 (IDH1) gene are among the most prevalent in low-grade gliomas and secondary glioblastoma. They lead to intracellular accumulation of the oncometabolite 2-hydroxyglutarate, represent an early pathogenic event and are considered a therapeutic target. Here we show, in this proof-of-concept study, that [1-C-13] alpha-ketoglutarate can serve as a metabolic imaging agent for non-invasive, real-time, in vivo monitoring of mutant IDH1 activity, and can inform on IDH1 status. Using C-13 magnetic resonance spectroscopy in combination with dissolution dynamic nuclear polarization, the metabolic fate of hyperpolarized [1-C-13] alpha-ketoglutarate is studied in isogenic glioblastoma cells that differ only in their IDH1 status. In lysates and tumours that express wild-type IDH1, only hyperpolarized [1-C-13] alpha-ketoglutarate can be detected. In contrast, in cells that express mutant IDH1, hyperpolarized [1-C-13] 2-hydroxyglutarate is also observed, both in cell lysates and in vivo in orthotopic tumours.