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 (4S)-4-(3-[F-18] fluoropropyl)-L-glutamate ([F-18] 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 [F-18] FSPG uptake, both in cells and in animal models of human ovarian cancer. We identified the mechanisms driving differential [F-18] FSPG cell accumulation and evaluated [F-18] 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 [F-18] FSPG cell accumulation in drug-resistant versus drug-sensitive cells. Decreased [F-18] FSPG uptake in drugresistant cells was a consequence of changes in intracellular cystine, a key precursor in GSH biosynthesis. In vivo, [F-18] FSPG uptake was decreased nearly 80% in chemotherapy- resistant A2780 tumors compared with parental drugsensitive tumors, with nonresponding tumors displaying high levels of oxidized-to-reduced GSH. Treatment of drugresistant A2780 tumors with doxorubicin resulted in no detectable change in tumor volume, GSH, or [F-18] FSPG uptake. Conclusions: This study demonstrates the ability of [F-18] FSPG to detect upregulated antioxidant pathways present in drug-resistant cancer. [F-18] 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.