Glutamine-based PET imaging facilitates enhanced metabolic evaluation of gliomas in vivo
Science Translational Medicine
11 Feb 2015
Vol 7, Issue 274
p. 274ra17
A PET approach to brain tumors
Positron emission tomography, or PET, is a common method of imaging tumors by detecting their uptake of a radioactively labeled tracer. Radiolabeled glucose, in particular, is often used for this type of imaging, because tumor cells are often highly dependent on glycolysis and require large amounts of glucose to maintain their metabolism. Unfortunately, this method cannot be used to image brain tumors, because regular brain cells are also highly dependent on glucose. Now, Venneti et al. have used mouse models and human patients to show that radiolabeled glutamine, which is also taken up by tumor cells, can be used to image brain tumors and distinguish them from normal brain and even from tumors that are no longer growing.
Abstract
Glucose and glutamine are the two principal nutrients that cancer cells use to proliferate and survive. Many cancers show altered glucose metabolism, which constitutes the basis for in vivo positron emission tomography (PET) imaging with 18F-fluorodeoxyglucose (18F-FDG). However, 18F-FDG is ineffective in evaluating gliomas because of high background uptake in the brain. Glutamine metabolism is also altered in many cancers, and we demonstrate that PET imaging in vivo with the glutamine analog 4-18F-(2S,4R)-fluoroglutamine (18F-FGln) shows high uptake in gliomas but low background brain uptake, facilitating clear tumor delineation. Chemo/radiation therapy reduced 18F-FGln tumor avidity, corresponding with decreased tumor burden. 18F-FGln uptake was not observed in animals with a permeable blood-brain barrier or neuroinflammation. We translated these findings to human subjects, where 18F-FGln showed high tumor/background ratios with minimal uptake in the surrounding brain in human glioma patients with progressive disease. These data suggest that 18F-FGln is avidly taken up by gliomas, can be used to assess metabolic nutrient uptake in gliomas in vivo, and may serve as a valuable tool in the clinical management of gliomas.
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Supplementary Material
Summary
Materials and Methods
Fig. S1. Glutamine is a major TCA cycle substrate and generates 2-HG.
Fig. S2. 19F-FGln is not metabolized in gliomas.
Fig. S3. 18F-FGln shows minimal, but specific, uptake in the normal brain.
Fig. S4. Mouse glioma models mimic human gliomas.
Fig. S5. Fasting and perfusion do not affect 18F-FGln uptake.
Fig. S6. 18F-FGln shows uptake in mouse glioma xenografts.
Fig. S7. Gln is metabolized to 2-HG without altering 18F-FGln uptake.
Fig. S8. Glioma animal models show 18F-FGln tumor uptake.
Fig. S9. Neuroinflammatory mouse models do not show 18F-FGln uptake.
Fig. S10. Chemoradiation decreases tumor burden and improves survival.
Fig. S11. Chemoradiation therapy results in increased gliosis.
Fig. S12. SLC1A5 partly mediates 18F-FGln uptake and is expressed in human gliomas.
Fig. S13. Patients imaged with 18F-FGln show glioma SLC1A5 expression.
Fig. S14. 18F-FGln shows uptake in a clinically progressive glioma.
Fig. S15. 18F-FGln does not show uptake in a clinically stable glioma.
Fig. S16. 18F-FGln shows clearance from blood and plasma.
Table S1. Patient characteristics.
Table S2. Comparison of 18F-FGln and 18F-FDG imaging in human subjects.
Table S3. Biodistribution of 18F-FGln in human subjects.
Table S4. 18F-FGln parent compound and radiometabolites in plasma at 1, 30, and 60 min after tracer injection.
Table S5. 18F-FGln dosimetry in human subjects.
Table S6. P values (provided as a separate Excel file).
Table S7. Data used to generate graphs (provided as a separate Excel file).
Resources
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Published In
Science Translational Medicine
Volume 7 | Issue 274
February 2015
February 2015
Copyright
Copyright © 2015, American Association for the Advancement of Science.
Submission history
Received: 16 October 2014
Accepted: 9 January 2015
Acknowledgments
We thank E. M. Burnazi and S. Cai of the MSKCC Radiochemistry and Molecular Imaging Probe Core; V. Longo of the MSKCC Small Animal Imaging Core; D. Yarilin of the MSKCC Cytology Core Facility; J. Chou and K. Panageas from the Epidemiology and Biostatistics program; P. Desai, Y. Koike, and A. Ku for technical assistance; A. Pedraza for maintaining and distributing glioma cell lines; and the MSKCC Organic Synthesis Core. We also thank A. Lashley and B. Gansukh for facilitating human studies and C. Le, M. Lupu, and D. Winkleman for animal MRI studies. We thank T. Lindsten, D. Pozega, and members of the Thompson Laboratory for critical reading of the manuscript. Funding: Supported by a Stand Up to Cancer Dream Team Translational Research Grant, grant number SU2C-AACR-DT0509 (C.B.T.). Stand Up to Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research. This work was supported by grants from the MSKCC Brain Tumor Center (S.V. and H.Z.), National Cancer Institute (NCI) K08 CA181475 (S.V.), National Institute of General Medical Sciences Medical Scientist Training Program (NIGMS MSTP) GM07739 (K.L.P.), National Institute of Neurological Disorders and Stroke (NINDS) F31 NS076028 (K.L.P.), NCI P50 CA086438 (J.S.L.), NIH R01 NS080944 (I.K.M.), and NCI R01-CA164490 (H.F.K). The MSKCC Cores were supported by the NIH Cancer Center Support Grant P30 CA08748 (C.B.T.). Author contributions: S.V., J.S.L, and C.B.T. conceived the experiments and wrote the paper. S.V. and H.Z. performed the animal experiments and analyzed the data. M.P.D. conducted the human subject study with guidance from A.M.O. and W.A.W. M.P.D., B.B., and P.Z. analyzed human data. K.L.P., C.C., S.D.C., D.R., I.K.M., G.L.R., and E.C.H. contributed to the animal experiments. M.P.D., H.Z., K.L.P., W.A.W., I.K.M., and H.F.K. provided critical insights. J.R.C. helped with the metabolism experiments, and C.W.B. helped in establishing cell lines. S.L., K.P., and H.F.K. enabled synthesis of the radioligand. Competing interests: C.B.T. is cofounder of Agios Pharmaceuticals and has financial interest in Agios. He is also a director of Charles River Laboratories and Merck Pharmaceuticals and owns stocks in these companies. H.F.K. is the CEO of Five Eleven Pharma, which has no conflict of interest with the subject matter in this manuscript. Data and materials availability: Patents have been filed concerning F-glutamine PET tracer preparation and imaging. These patents do not restrict the research or noncommercial use of the probe or technique.
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