Assessment of tumor redox status through (S)-4-(3-[ 
            18 F]fluoropropyl)-L-glutamic acid PET imaging of system x
            c activity

Patrick McCormick; Hannah E. Greenwood; Matthias  Glaser; Oliver D.K. Maddocks; Thibault Gendron; Kerstin Sander; Gayatri Gowrishankar; Aileen Hoehne; Tong Zhang; Adam J. Shuhendler; David Y. Lewis; Mathias Berndt; Norman Koglin; Mark Lythgoe; Sanjiv S. Gambhir; Erik Arstad; Tim Witney

doi:10.1158/0008-5472.CAN-18-2634

Assessment of tumor redox status through (S)-4-(3-[ ¹⁸ F]fluoropropyl)-L-glutamic acid PET imaging of system x _c activity

Patrick McCormick, Hannah E. Greenwood, Matthias Glaser, Oliver D.K. Maddocks, Thibault Gendron, Kerstin Sander, Gayatri Gowrishankar, Aileen Hoehne, Tong Zhang, Adam J. Shuhendler, David Y. Lewis, Mathias Berndt, Norman Koglin, Mark Lythgoe, Sanjiv S. Gambhir, Erik Arstad, Tim Witney

Imaging Chemistry & Biology

UCL University College London

Research output: Contribution to journal › Article › peer-review

40 Citations (Scopus)

259 Downloads (Pure)

Abstract

The cell's endogenous antioxidant system is vital to maintenance of redox homeostasis. Despite its central role in normal and pathophysiology, no non-invasive tools exist to measure this system in patients. The cystine/glutamate antiporter system xc- maintains the balance between intracellular reactive oxygen species and antioxidant production through the provision of cystine, a key precursor in glutathione biosynthesis. Here we show that tumor cell retention of a system xc--specific positron emission tomography radiotracer, (S)-4-(3-[18F]fluoropropyl)-L-glutamic acid ([18F]FSPG), decreases in proportion to levels of oxidative stress following treatment with a range of redox-active compounds. The decrease in [18F]FSPG retention correlated with a depletion of intracellular cystine resulting from increased de novo glutathione biosynthesis, shown through [U-13C6, U-15N2]cystine isotopic tracing. In vivo, treatment with the chemotherapeutic doxorubicin decreased [18F]FSPG tumor uptake in a mouse model of ovarian cancer, coinciding with markers of oxidative stress but preceding tumor shrinkage and decreased glucose utilization. Having already been used in pilot clinical trials, [18F]FSPG PET could be rapidly translated to the clinic as an early redox indicator of tumor response to treatment.

Original language	English
Article number	79
Pages (from-to)	853-863
Number of pages	11
Journal	Cancer Research
Volume	79
Issue number	4
Early online date	6 Nov 2018
DOIs	https://doi.org/10.1158/0008-5472.CAN-18-2634
Publication status	Published - 15 Feb 2019

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Assessment of tumor redox_MCCORMICK_Firstonline6November2018_GREEN AAMAccepted author manuscript, 16.5 MB
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McCormick, P., Greenwood, H. E., Glaser, M., Maddocks, O. D. K., Gendron, T., Sander, K., Gowrishankar, G., Hoehne, A., Zhang, T., Shuhendler, A. J., Lewis, D. Y., Berndt, M., Koglin, N., Lythgoe, M., Gambhir, S. S., Arstad, E., & Witney, T. (2019). Assessment of tumor redox status through (S)-4-(3-[ ¹⁸ F]fluoropropyl)-L-glutamic acid PET imaging of system x _c activity. Cancer Research, 79(4), 853-863. Article 79. https://doi.org/10.1158/0008-5472.CAN-18-2634

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title = "Assessment of tumor redox status through (S)-4-(3-[ 18 F]fluoropropyl)-L-glutamic acid PET imaging of system x c activity",

abstract = "The cell's endogenous antioxidant system is vital to maintenance of redox homeostasis. Despite its central role in normal and pathophysiology, no non-invasive tools exist to measure this system in patients. The cystine/glutamate antiporter system xc- maintains the balance between intracellular reactive oxygen species and antioxidant production through the provision of cystine, a key precursor in glutathione biosynthesis. Here we show that tumor cell retention of a system xc--specific positron emission tomography radiotracer, (S)-4-(3-[18F]fluoropropyl)-L-glutamic acid ([18F]FSPG), decreases in proportion to levels of oxidative stress following treatment with a range of redox-active compounds. The decrease in [18F]FSPG retention correlated with a depletion of intracellular cystine resulting from increased de novo glutathione biosynthesis, shown through [U-13C6, U-15N2]cystine isotopic tracing. In vivo, treatment with the chemotherapeutic doxorubicin decreased [18F]FSPG tumor uptake in a mouse model of ovarian cancer, coinciding with markers of oxidative stress but preceding tumor shrinkage and decreased glucose utilization. Having already been used in pilot clinical trials, [18F]FSPG PET could be rapidly translated to the clinic as an early redox indicator of tumor response to treatment.",

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McCormick, P, Greenwood, HE, Glaser, M, Maddocks, ODK, Gendron, T, Sander, K, Gowrishankar, G, Hoehne, A, Zhang, T, Shuhendler, AJ, Lewis, DY, Berndt, M, Koglin, N, Lythgoe, M, Gambhir, SS, Arstad, E & Witney, T 2019, 'Assessment of tumor redox status through (S)-4-(3-[ ¹⁸ F]fluoropropyl)-L-glutamic acid PET imaging of system x _c activity', Cancer Research, vol. 79, no. 4, 79, pp. 853-863. https://doi.org/10.1158/0008-5472.CAN-18-2634

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AU - McCormick, Patrick

AU - Greenwood, Hannah E.

AU - Glaser, Matthias

AU - Maddocks, Oliver D.K.

AU - Gendron, Thibault

AU - Sander, Kerstin

AU - Gowrishankar, Gayatri

AU - Hoehne, Aileen

AU - Zhang, Tong

AU - Shuhendler, Adam J.

AU - Lewis, David Y.

AU - Berndt, Mathias

AU - Koglin, Norman

AU - Lythgoe, Mark

AU - Gambhir, Sanjiv S.

AU - Arstad, Erik

AU - Witney, Tim

PY - 2019/2/15

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N2 - The cell's endogenous antioxidant system is vital to maintenance of redox homeostasis. Despite its central role in normal and pathophysiology, no non-invasive tools exist to measure this system in patients. The cystine/glutamate antiporter system xc- maintains the balance between intracellular reactive oxygen species and antioxidant production through the provision of cystine, a key precursor in glutathione biosynthesis. Here we show that tumor cell retention of a system xc--specific positron emission tomography radiotracer, (S)-4-(3-[18F]fluoropropyl)-L-glutamic acid ([18F]FSPG), decreases in proportion to levels of oxidative stress following treatment with a range of redox-active compounds. The decrease in [18F]FSPG retention correlated with a depletion of intracellular cystine resulting from increased de novo glutathione biosynthesis, shown through [U-13C6, U-15N2]cystine isotopic tracing. In vivo, treatment with the chemotherapeutic doxorubicin decreased [18F]FSPG tumor uptake in a mouse model of ovarian cancer, coinciding with markers of oxidative stress but preceding tumor shrinkage and decreased glucose utilization. Having already been used in pilot clinical trials, [18F]FSPG PET could be rapidly translated to the clinic as an early redox indicator of tumor response to treatment.

AB - The cell's endogenous antioxidant system is vital to maintenance of redox homeostasis. Despite its central role in normal and pathophysiology, no non-invasive tools exist to measure this system in patients. The cystine/glutamate antiporter system xc- maintains the balance between intracellular reactive oxygen species and antioxidant production through the provision of cystine, a key precursor in glutathione biosynthesis. Here we show that tumor cell retention of a system xc--specific positron emission tomography radiotracer, (S)-4-(3-[18F]fluoropropyl)-L-glutamic acid ([18F]FSPG), decreases in proportion to levels of oxidative stress following treatment with a range of redox-active compounds. The decrease in [18F]FSPG retention correlated with a depletion of intracellular cystine resulting from increased de novo glutathione biosynthesis, shown through [U-13C6, U-15N2]cystine isotopic tracing. In vivo, treatment with the chemotherapeutic doxorubicin decreased [18F]FSPG tumor uptake in a mouse model of ovarian cancer, coinciding with markers of oxidative stress but preceding tumor shrinkage and decreased glucose utilization. Having already been used in pilot clinical trials, [18F]FSPG PET could be rapidly translated to the clinic as an early redox indicator of tumor response to treatment.

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UR - http://cancerres.aacrjournals.org/

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DO - 10.1158/0008-5472.CAN-18-2634

M3 - Article

SN - 0008-5472

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IS - 4

M1 - 79

ER -

Assessment of tumor redox status through (S)-4-(3-[ ¹⁸ F]fluoropropyl)-L-glutamic acid PET imaging of system x _c activity

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