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 radiotracer (4)-4-(3-[F]fluoropropyl)-l-glutamate ([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 [F]FSPG uptake, both in cells and in animal models of human ovarian cancer. We identified the mechanisms driving differential [F]FSPG cell accumulation and evaluated [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 [F]FSPG cell accumulation in drug-resistant versus drug-sensitive cells. Decreased [F]FSPG uptake in drug-resistant cells was a consequence of changes in intracellular cystine, a key precursor in GSH biosynthesis. , [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 [F]FSPG uptake.

Conclusions: This study demonstrates the ability of [F]FSPG to detect upregulated antioxidant pathways present in drug-resistant cancer. [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.