Measurement of tumor antioxidant capacity and prediction of chemotherapy resistance in preclinical models of ovarian cancer by positron emission tomography

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.