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 xc - radiotracer (4S)-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. In vivo, [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.
Highlights
High-grade serous ovarian cancer (HGSOC) is a devastating disease with a 5-year survival rate of less than 42% [1]
In vivo, [18F]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 [18F]FSPG
Summary
High-grade serous ovarian cancer (HGSOC) is a devastating disease with a 5-year survival rate of less than 42% [1]. Despite initial rates of response to platinum-based chemotherapy of over 80%, the median progression-free survival is just 18 months [2, 3]. Response to platinum treatment in patients with ovarian cancer is measured as the length of time from treatment to relapse, known as the platinum-free interval PFI, is a crude measure of drug sensitivity [6] and is poor at predicting response for patients identified as "partially sensitive." These patients relapse 6 to 12 months after first-line treatment and will all subsequently receive further platinum-based treatment, despite benefit only being appreciable in 27% to 33% of cases [7]. The ability to identify patients refractive to the standard of care will enable the clinician to select the most appropriate second-line therapy for the individual patient, such as targeted therapy (e.g., PARP inhibitors) or biologics (e.g., bevacizumab)
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