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

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          Abstract

          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 (R 2=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.

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          Author and article information

          Journal
          2984705R
          2786
          Cancer Res
          Cancer Res.
          Cancer research
          0008-5472
          1538-7445
          1 February 2017
          15 February 2017
          15 March 2017
          15 March 2018
          : 77
          : 6
          : 1476-1484
          Article
          PMC5362115 PMC5362115 5362115 nihpa847256
          10.1158/0008-5472.CAN-16-1945
          5362115
          28202527
          Categories
          Article

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