[(18)F](2S,4R)4-Fluoroglutamine PET Detects Glutamine Pool Size Changes in Triple-Negative Breast Cancer in Response to Glutaminase Inhibition.
[(18)F](2S,4R)4-Fluoroglutamine PET Detects Glutamine Pool Size Changes in Triple-Negative Breast Cancer in Response to Glutaminase Inhibition.
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DOI：
10.1158/0008-5472.can-16-1945
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发表时间：
2017-03-15
期刊：
影响因子：
11.2
通讯作者：
Mankoff DA
中科院分区：
文献类型：
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作者：
Zhou R;Pantel AR;Li S;Lieberman BP;Ploessl K;Choi H;Blankemeyer E;Lee H;Kung HF;Mach RH;Mankoff DA
谷氨酰胺分解是许多侵袭性癌症（包括三阴性乳腺癌（TNBC））采用的一种代谢途径，利用谷氨酰胺来维持生存和生长。在本研究中，我们检查了 [18F](2S,4R)4-氟谷氨酰胺 ([18F]4F-Gln) PET 测量肿瘤细胞谷氨酰胺池大小的效用，其变化可能揭示针对这种癌症特异性代谢途径的药物的药效 (PD) 效应。 TNBC 肿瘤中的高谷氨酰胺酶 (GLS) 活性导致通过高分辨率 1H 磁共振波谱 (MRS) 测定的细胞谷氨酰胺库大小较低。 GLS 抑制显着增加了 TNBC 肿瘤中谷氨酰胺池的大小。与 TNBC 相比，MCF-7 肿瘤本质上具有较低的 GLS 活性，显示出较大的基线谷氨酰胺库大小，并且不会因 GLS 抑制而发生太大变化。从 [18F]4F-Gln PET 图像获得的肿瘤与血液活性比 (T/B) 与基线时两种肿瘤模型的不同谷氨酰胺池大小相匹配。经过短期的 GLS 抑制剂治疗后，TNBC 中的 T/B 值显着增加，但 MCF-7 肿瘤中的 T/B 值没有变化。在两种肿瘤类型中以及 GLS 抑制剂或载体治疗后，我们观察到 T/B 值与使用 MRS 测量的肿瘤谷氨酰胺池大小之间存在很强的正相关性 (R2=0.71)。总之，[18F]4F-Gln PET 追踪了具有差异 GLS 活性的乳腺癌细胞谷氨酰胺池大小，并检测到 GLS 抑制剂诱导的细胞谷氨酰胺池大小增加。这项研究完成了验证 [18F]4F-Gln PET 作为谷氨酰胺酶靶向药物的 PD 标记物的第一步必要步骤。
Glutaminolysis is a metabolic pathway adapted by many aggressive cancers, including triple-negative breast cancers (TNBC), to utilize glutamine for survival and growth. In this study, we examined the utility of [18F](2S,4R)4-fluoroglutamine ([18F]4F-Gln) PET to measure tumor cellular glutamine pool size, whose change might reveal the pharmacodynamic (PD) effect of drugs targeting this cancer-specific metabolic pathway. High glutaminase (GLS) activity in TNBC tumors resulted in low cellular glutamine pool size assayed via high-resolution 1H magnetic resonance spectroscopy (MRS). GLS inhibition significantly increased glutamine pool size in TNBC tumors. MCF-7 tumors, with inherently low GLS activity compared to TNBC, displayed a larger baseline glutamine pool size that did not change as much in response to GLS inhibition. The tumor-to-blood-activity-ratios (T/B) obtained from [18F]4F-Gln PET images matched the distinct glutamine pool sizes of both tumor models at baseline. After a short course of GLS inhibitor treatment, the T/B values increased significantly in TNBC, but did not change in MCF-7 tumors. Across both tumor types and after GLS inhibitor or vehicle treatment, we observed a strong positive correlation between T/B values and tumor glutamine pool size measured using MRS (R2=0.71). In conclusion, [18F]4F-Gln PET tracked cellular glutamine pool size in breast cancers with differential GLS activity and detected increases in cellular glutamine pool size induced by GLS inhibitors. This study accomplished the first necessary step towards validating [18F]4F-Gln PET as a PD marker for glutaminase-targeting drugs.