Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, California.
Department of Neurological Surgery, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California.
Cancer Res. 2020 Nov 15;80(22):5098-5108. doi: 10.1158/0008-5472.CAN-20-1314. Epub 2020 Sep 21.
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, 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 temozolomide in both genetically engineered and patient-derived mutant IDH1 models. Using H MRS in combination with chemometrics identified several metabolic alterations in temozolomide-treated cells, including a significant increase in steady-state glutamate levels. This was confirmed , where the observed H MRS increase in glutamate/glutamine occurred prior to tumor shrinkage. Cells labeled with [1-C]glucose and [3-C]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 temozolomide treatment. In line with these results, hyperpolarized [5-C]glutamate produced from [2-C]pyruvate and hyperpolarized [1-C]glutamate produced from [1-C]α-ketoglutarate were significantly higher in temozolomide-treated cells compared with controls. Collectively, our findings identify H MRS-detectable elevation of glutamate and hyperpolarized C MRS-detectable glutamate production from either pyruvate or α-ketoglutarate as potential translatable metabolic biomarkers of response to temozolomide treatment in mutant IDH1 glioma. SIGNIFICANCE: These findings show that glutamate can be used as a noninvasive, imageable metabolic marker for early assessment of tumor response to temozolomide, with the potential to improve treatment strategies for mutant IDH1 patients.
尽管低级别的神经胶质瘤是由异柠檬酸脱氢酶 1（IDH1）基因突变驱动的，并且比原发性胶质母细胞瘤的侵袭性低，但它们仍然会复发。IDH1 突变患者越来越多地接受替莫唑胺治疗，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治疗前肿瘤缩小之前的反应。本研究的目的是确定磁共振波谱（MRS）基于代谢变化对基因工程和患者衍生的突变 IDH1 模型中替莫唑胺反应的检测价值。使用 H MRS 结合化学计量学方法，在替莫唑胺处理的细胞中鉴定出几种代谢改变，包括稳态谷氨酸水平的显著增加。这一点得到了证实，观察到的谷氨酸/谷氨酰胺的 H MRS 增加发生在肿瘤缩小之前。用 [1-C]葡萄糖和 [3-C]谷氨酰胺标记的细胞，细胞内谷氨酸的主要来源，表明替莫唑胺治疗后，谷氨酸从葡萄糖通过三羧酸循环以及从谷氨酰胺的通量均增加。与这些结果一致，从 [2-C]丙酮酸产生的极化 [5-C]谷氨酸和从 [1-C]α-酮戊二酸产生的极化 [1-C]谷氨酸在替莫唑胺处理的细胞中明显高于对照。总之，我们的研究结果确定了 H MRS 可检测到的谷氨酸升高和 H MRS 可检测到的来自丙酮酸或α-酮戊二酸的极化 C MRS 检测到的谷氨酸产生可作为突变 IDH1 神经胶质瘤对替莫唑胺治疗反应的潜在可转化代谢生物标志物。意义：这些发现表明，谷氨酸可以用作非侵入性、可成像的代谢标志物，用于早期评估肿瘤对替莫唑胺的反应，有可能改善突变 IDH1 患者的治疗策略。
