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Purpose: Drug resistance is a major obstacle for the effective treatment of patients with high-grade serous ovarian cancer (HGSOC). Currently, there is no satisfactory way to identify patients with HGSOC that are refractive to the standard of care. Here, we propose the system x c - radiotracer (4 S )-4-(3-[ 18 F]fluoropropyl)-l-glutamate ([ 18 F]FSPG) as a non-invasive method to measure upregulated antioxidant pathways present in drug-resistant HGSOC., Experimental Design: Using matched chemotherapy sensitive and resistant ovarian cancer cell lines, we assessed their antioxidant capacity and its relation to [ 18 F]FSPG uptake, both in cells and in animal models of human ovarian cancer. We identified the mechanisms driving differential [ 18 F]FSPG cell accumulation and evaluated [ 18 F]FSPG tumor uptake as predictive marker of treatment response in drug-resistant tumors., Results: High intracellular glutathione (GSH) and low reactive oxygen species corresponded to decreased [ 18 F]FSPG cell accumulation in drug-resistant versus drug-sensitive cells. Decreased [ 18 F]FSPG uptake in drug-resistant cells was a consequence of changes in intracellular cystine, a key precursor in GSH biosynthesis. In vivo , [ 18 F]FSPG uptake was decreased nearly 80% in chemotherapy-resistant A2780 tumors compared with parental drug-sensitive tumors, with nonresponding tumors displaying high levels of oxidized-to-reduced GSH. Treatment of drug-resistant A2780 tumors with doxorubicin resulted in no detectable change in tumor volume, GSH, or [ 18 F]FSPG uptake., Conclusions: This study demonstrates the ability of [ 18 F]FSPG to detect upregulated antioxidant pathways present in drug-resistant cancer. [ 18 F]FSPG may therefore enable the identification of patients with HGSOC that are refractory to standard of care, allowing the transferal of drug-resistant patients to alternative therapies, thereby improving outcomes in this disease., (©2019 American Association for Cancer Research.)

The cell's endogenous antioxidant system is vital to maintenance of redox homeostasis. Despite its central role in normal and pathophysiology, no noninvasive 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 PET 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. SIGNIFICANCE: [ 18 F]FSPG PET imaging provides a sensitive noninvasive measure of tumor redox status and provides an early marker of tumor response to therapy. See related commentary by Lee et al., p. 701 ., (©2018 American Association for Cancer Research.)