[18F]（2S，4R）4-氟谷氨酰胺PET检测到谷氨酰胺酶抑制反应在三阴性乳腺癌中谷氨酰胺库的大小变化。,Cancer Research

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[18F]（2S，4R）4-氟谷氨酰胺PET检测到谷氨酰胺酶抑制反应在三阴性乳腺癌中谷氨酰胺库的大小变化。
Cancer Research ( IF 12.5 ) Pub Date : 2017-02-17 , DOI: 10.1158/0008-5472.can-16-1945
Rong Zhou ₁ , Austin R Pantel ₁ , Shihong Li ₁ , Brian P Lieberman ₁ , Karl Ploessl ₁ , Hoon Choi ₁ , Eric Blankemeyer ₁ , Hsiaoju Lee ₁ , Hank F Kung ₁ , Robert H Mach ₁ , David A Mankoff ₁

Affiliation

谷氨酰胺分解是一种被许多侵袭性癌症（包括三阴性乳腺癌（TNBC））适应的代谢途径，以利用谷氨酰胺维持生存和生长。在这项研究中，我们研究了[18F]（2S，4R）4-氟谷氨酰胺（[18F] 4F-Gln）PET用来测量肿瘤细胞谷氨酰胺库大小的实用性，其变化可能揭示靶向药物的药效（PD）效应这种癌症特有的代谢途径。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）测定的低细胞谷氨酰胺池大小。GLS抑制显着增加TNBC肿瘤中的谷氨酰胺库大小。与TNBC相比，具有固有较低的GLS活性的MCF-7肿瘤显示出较大的基线谷氨酰胺库大小，但对GLS抑制的响应变化不大。从[18F] 4F-Gln PET图像获得的肿瘤与血液的活性比（T / B）与两种肿瘤模型在基线时的不同谷氨酰胺库大小相匹配。经过短暂的GLS抑制剂治疗后，TNBC中的T / B值显着增加，而MCF-7肿瘤中的T / B值没有变化。在两种肿瘤类型之间以及在GLS抑制剂或媒介物治疗后，我们观察到T / B值与使用MRS测量的肿瘤谷氨酰胺库大小之间存在很强的正相关（r2 = 0.71）。总之，[18F] 4F-Gln PET追踪具有不同GLS活性的乳腺癌细胞的谷氨酰胺库大小，并检测到GLS抑制剂诱导的细胞谷氨酰胺库大小增加。这项研究完成了朝[18F] 4F-Gln PET验证作为靶向GLS的药物的PD标志物迈出的第一步。癌症研究；77（6）；1476-84。©2017 AACR。

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[18F](2S,4R)4-Fluoroglutamine PET Detects Glutamine Pool Size Changes in Triple-Negative Breast Cancer in Response to Glutaminase Inhibition.

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 with 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 toward validating [18F]4F-Gln PET as a PD marker for GLS-targeting drugs. Cancer Res; 77(6); 1476-84. ©2017 AACR.

更新日期：2019-11-01

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