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

Journal Article · Wed Feb 15 00:00:00 EST 2017 · Cancer Research

DOI:https://doi.org/10.1158/0008-5472.CAN-16-1945· OSTI ID:1462347

Zhou, Rong ^[1]; Pantel, Austin R. ^[1]; Li, Shihong ^[1]; Lieberman, Brian P. ^[1]; Ploessl, Karl ^[1]; Choi, Hoon ^[1]; Blankemeyer, Eric ^[1]; Lee, Hsiaoju ^[1]; Kung, Hank F. ^[1]; Mach, Robert H. ^[1]; Mankoff, David A. ^[1]

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1. Univ. of Pennsylvania, Philadelphia, PA (United States). Dept. of Radiology

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 work accomplished the first necessary step towards validating [¹⁸F]4F-Gln PET as a PD marker for glutaminase-targeting drugs.

• Research Organization: Univ. of Pennsylvania, Philadelphia, PA (United States)
• Sponsoring Organization: USDOE; Susan G. Komen Foundation
• Contributing Organization: Calithera Biosciences, Inc., San Francisco, CA (United States)
• Grant/Contract Number: SC0012476; SAC140060; R21-CA-198563; R01CA211337; T32-EB004311
• OSTI ID: 1462347
• Journal Information: Cancer Research, Vol. 77, Issue 6; ISSN 0008-5472
• Publisher: American Association for Cancer Research
• Country of Publication: United States
• Language: English

Related Subjects

62 RADIOLOGY AND NUCLEAR MEDICINE
Glutamine
Glutaminase
Triple Negative Breast Cancer
PET
MRS
Glutaminolysis
Precision Medicine