Assessment of tumor redox status through (S)-4-(3-[18F]fluoropropyl)-l-glutamic acid positron emission tomography imaging of system xc- activity

• Published in: Cancer research (Chicago, Ill.) Vol. 79; no. 4; pp. 853 - 863
• Main Authors: McCormick, Patrick N., Greenwood, Hannah E., Glaser, Matthias, Maddocks, Oliver D.K., Gendron, Thibault, Sander, Kerstin, Gowrishankar, Gayatri, Hoehne, Aileen, Zhang, Tong, Shuhendler, Adam J., Lewis, David Y., Berndt, Mathias, Koglin, Norman, Lythgoe, Mark F., Gambhir, Sanjiv S., Årstad, Erik, Witney, Timothy H.
• Format: Journal Article
• Language: English
• Published: 06.11.2018
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-18-2634

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 x c - 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 x c - -specific positron emission tomography radiotracer, ( S )-4-(3-[ 18 F]fluoropropyl)- l -glutamic acid ([ 18 F]FSPG), decreases in proportion to levels of oxidative stress following treatment with a range of redox-active compounds. The decrease in [ 18 F]FSPG retention correlated with a depletion of intracellular cystine resulting from increased de novo glutathione biosynthesis, shown through [U- 13 C 6 , U- 15 N 2 ]cystine isotopic tracing. In vivo , treatment with the chemotherapeutic doxorubicin decreased [ 18 F]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, [ 18 F]FSPG PET could be rapidly translated to the clinic as an early redox indicator of tumor response to treatment.