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

Hannah Greenwood, Patrick McCormick, Thibault Gendron, Matthias Glaser, Raul Geraldo Pereira, Oliver Maddocks, Kerstin Sander, Tong Zhang, Norman Koglin, Mark Lythgoe, Erik Årstad, Daniel Hochhauser, Timothy Howard Witney

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29 Citations (Scopus)
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Abstract

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 HGSOC patients 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.
Experimental Design: 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.
Results: 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 ~80% in chemotherapy-resistant A2780 tumors compared to parental drug-sensitive tumors, with non-responding tumors displaying high levels of oxidised-to-reduced GSH. Treatment of drug-resistant A2780 tumors with doxorubicin resulted in no detectable change in tumor volume, GSH or [18F]FSPG uptake.
Conclusions: 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 HGSOC patients that are refractory to standard-of-care, allowing the transferral of drug-resistant patients to alternative therapies, thereby improving outcomes in this disease.
Original languageEnglish
Pages (from-to)2471-2482
Number of pages12
JournalClinical Cancer Research
Volume25
Issue number8
Early online date16 Jan 2019
DOIs
Publication statusPublished - 15 Apr 2019

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