Glutamate Is a Noninvasive Metabolic Biomarker of IDH1-Mutant Glioma Response to Temozolomide Treatment.
Glutamate Is a Noninvasive Metabolic Biomarker of IDH1-Mutant Glioma Response to Temozolomide Treatment.
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谷氨酸是idh1突变型胶质瘤对替莫唑胺治疗反应的无创代谢生物标志物。
DOI：
10.1158/0008-5472.can-20-1314
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发表时间：
2020-11-15
期刊：
影响因子：
11.2
通讯作者：
Ronen SM
中科院分区：
文献类型：
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作者：
Subramani E;Radoul M;Najac C;Batsios G;Molloy AR;Hong D;Gillespie AM;Santos RD;Viswanath P;Costello JF;Pieper RO;Ronen SM
虽然低级别胶质瘤是由异柠檬酸脱氢酶1（IDH 1）基因突变驱动的，并且比原发性胶质母细胞瘤侵袭性低，但它们通常会复发。IDH 1突变患者越来越多地接受替莫唑胺（TMZ）治疗，但早期检测反应仍然是一个挑战，需要补充成像方法来评估肿瘤缩小前对治疗的反应。本研究的目的是确定基于磁共振波谱（MRS）的代谢变化在基因工程和患者来源的突变IDH 1模型中检测TMZ反应的价值。使用1H MRS结合化学计量学确定了TMZ处理的细胞中的几个代谢改变，包括稳态谷氨酸水平的显着增加。这在体内得到了证实，其中观察到的谷氨酸/谷氨酰胺的1H MRS增加发生在肿瘤缩小之前。用[1- 13 C]葡萄糖和[3- 13 C]谷氨酰胺（细胞谷氨酸的主要来源）标记的细胞显示，TMZ处理后，通过三羧酸循环从葡萄糖和谷氨酰胺到谷氨酸的通量增加。与这些结果一致，与对照组相比，TMZ处理的细胞中由[2- 13 C]丙酮酸产生的超极化[5- 13 C]谷氨酸和由[1- 13 C]α-酮戊二酸产生的超极化[1- 13 C]谷氨酸显著更高。总的来说，我们的研究结果确定了1H MRS可检测的谷氨酸升高和超极化13 C MRS可检测的丙酮酸或α-酮戊二酸的谷氨酸产生作为突变IDH 1胶质瘤对TMZ治疗反应的潜在可翻译代谢生物标志物。
Although lower-grade gliomas are driven by mutations in the isocitrate dehydrogenase 1 (IDH1) gene and are less aggressive than primary glioblastoma, they nonetheless generally recur. IDH1 mutant patients are increasingly being treated with temozolomide (TMZ), but early detection of response remains a challenge and there is a need for complementary imaging methods to assess response to therapy prior to tumor shrinkage. The goal of this study was to determine the value of magnetic resonance spectroscopy (MRS)-based metabolic changes for detection of response to TMZ in both genetically engineered and patient-derived mutant IDH1 models. Using 1H MRS in combination with chemometrics identified several metabolic alterations in TMZ-treated cells, including a significant increase in steady-state glutamate levels. This was confirmed in vivo, where the observed 1H MRS increase in glutamate/glutamine occurred prior to tumor shrinkage. Cells labeled with [1-13C]glucose and [3-13C]glutamine, the principal sources of cellular glutamate, showed that flux to glutamate both from glucose via the tricarboxylic acid cycle and from glutamine were increased following TMZ treatment. In line with these results, hyperpolarized [5-13C]glutamate produced from [2-13C]pyruvate and hyperpolarized [1-13C]glutamate produced from [1-13C]α-ketoglutarate were significantly higher in TMZ-treated cells compared to controls. Collectively, our findings identify 1H MRS-detectable elevation of glutamate and hyperpolarized 13C MRS-detectable glutamate production from either pyruvate or α-ketoglutarate as potential translatable metabolic biomarkers of response to TMZ treatment in mutant IDH1 glioma.