title: [18F](2S,4R)4-Fluoroglutamine PET Detects Glutamine Pool Size Changes in Triple-Negative Breast Cancer in Response to Glutaminase Inhibition.
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-resolution1H 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.
authors.affiliation: Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania. rongzhou@upenn.edu david.mankoff@uphs.upenn.edu.
authors.forename: Rong
authors.initials: R
authors.lastname: Zhou
authors.affiliation: Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Austin R
authors.initials: AR
authors.lastname: Pantel
authors.affiliation: Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Shihong
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Lieberman
authors.affiliation: Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Karl
authors.initials: K
authors.lastname: Ploessl
authors.affiliation: Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Hoon
authors.initials: H
authors.lastname: Choi
authors.affiliation: Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Eric
authors.initials: E
authors.lastname: Blankemeyer
authors.affiliation: Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Hsiaoju
authors.initials: H
authors.lastname: Lee
authors.affiliation: Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Hank F
authors.initials: HF
authors.lastname: Kung
authors.affiliation: Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Mach
authors.affiliation: Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania. rongzhou@upenn.edu david.mankoff@uphs.upenn.edu.
authors.forename: David A
authors.initials: DA
authors.lastname: Mankoff
mesh_terms: D000818:Animals; D005260:Female; D005972:Glutaminase / Q000037:antagonists & inhibitors*; D005973:Glutamine / Q000031:analogs & derivatives* / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D049268:Positron-Emission Tomography; D064726:Triple Negative Breast Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism* / Q000473:pathology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C569565:4-fluoroglutamine; D005973:Glutamine; D005972:Glutaminase