Metabolic subtypes of glioblastoma have different prognoses and responses to treatment. Deuterium metabolic imaging with 2H-labeled substrates is a potential approach to stratify patients into metabolic subtypes for targeted treatment. Here, we used 2H magnetic resonance spectroscopy (MRS) and spectroscopic imaging (MRSI) measurements of [6,6’-2H2]glucose metabolism to identify metabolic subtypes and their responses to chemoradiotherapy in patient-derived glioblastoma xenografts in vivo. The metabolism of patient-derived cells was first characterized in vitro by measuring the oxygen consumption rate, a marker of mitochondrial TCA cycle activity, as well as the extracellular acidification rate and 2H-labeled lactate production from [6,6’-2H2]glucose, which are markers of glycolytic activity. Two cell lines representative of a glycolytic subtype and two representative of a mitochondrial subtype were identified. 2H MRS and MRSI measurements showed similar concentrations of 2H-labeled glucose from [6,6’-2H2]glucose in all four tumor models when implanted orthotopically in mice. The glycolytic subtypes showed higher concentrations of 2H-labeled lactate than the mitochondrial subtypes and normal-appearing brain tissue, whereas the mitochondrial subtypes showed more glutamate/glutamine labeling, a surrogate for TCA cycle activity, than the glycolytic subtypes and normal-appearing brain tissue. The response of the tumors to chemoradiation could be detected within 24 hours of treatment completion, with the mitochondrial subtypes showing a decrease in both 2H-labeled glutamate/glutamine and lactate concentrations and glycolytic tumors showing a decrease in 2H-labeled lactate concentration. This technique has the potential to be used clinically for treatment selection and early detection of treatment response.

中文翻译：

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氘代谢成像可区分胶质母细胞瘤代谢亚型并检测放化疗的早期反应

胶质母细胞瘤的代谢亚型具有不同的预后和对治疗的反应。使用 2H 标记底物进行氘代谢成像是将患者分为代谢亚型以进行靶向治疗的潜在方法。在这里，我们使用 [6,6'-2H2] 葡萄糖代谢的 2H 磁共振波谱 (MRS) 和光谱成像 (MRSI) 测量来识别患者来源的胶质母细胞瘤异种移植体内的代谢亚型及其对放化疗的反应。首先通过测量耗氧率（线粒体 TCA 循环活性的标志）以及细胞外酸化率和 [6,6'-2H2] 葡萄糖产生 2H 标记的乳酸来在体外表征患者来源细胞的代谢，它们是糖酵解活性的标记。鉴定了代表糖酵解亚型的两种细胞系和代表线粒体亚型的两种细胞系。 2H MRS 和 MRSI 测量显示，当原位植入小鼠体内时，所有四种肿瘤模型中[6,6'-2H2]葡萄糖的 2H 标记葡萄糖浓度相似。糖酵解亚型比线粒体亚型和正常脑组织显示出更高浓度的 2H 标记乳酸，而线粒体亚型比糖酵解亚型和正常脑组织显示出更多的谷氨酸/谷氨酰胺标记（TCA 循环活性的替代物） 。治疗完成后 24 小时内即可检测到肿瘤对放化疗的反应，线粒体亚型显示 2H 标记的谷氨酸/谷氨酰胺和乳酸浓度降低，糖酵解肿瘤显示 2H 标记的乳酸浓度降低。该技术有潜力在临床上用于治疗选择和治疗反应的早期检测。