Measurement of Tumor Antioxidant Capacity and Prediction of Chemotherapy Resistance in Preclinical Models of Ovarian Cancer by Positron Emission Tomography.

Abstract

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<i>S</i>)-4-(3-[¹⁸F]fluoropropyl)-l-glutamate ([¹⁸F]FSPG) as a non-invasive method to measure upregulated antioxidant pathways present in drug-resistant HGSOC. Using matched chemotherapy sensitive and resistant ovarian cancer cell lines, we assessed their antioxidant capacity and its relation to [¹⁸F]FSPG uptake, both in cells and in animal models of human ovarian cancer. We identified the mechanisms driving differential [¹⁸F]FSPG cell accumulation and evaluated [¹⁸F]FSPG tumor uptake as predictive marker of treatment response in drug-resistant tumors. High intracellular glutathione (GSH) and low reactive oxygen species corresponded to decreased [¹⁸F]FSPG cell accumulation in drug-resistant versus drug-sensitive cells. Decreased [¹⁸F]FSPG uptake in drug-resistant cells was a consequence of changes in intracellular cystine, a key precursor in GSH biosynthesis. <i>In vivo</i>, [¹⁸F]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 [¹⁸F]FSPG uptake. This study demonstrates the ability of [¹⁸F]FSPG to detect upregulated antioxidant pathways present in drug-resistant cancer. [¹⁸F]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.