Measurement of Tumor Antioxidant Capacity and Prediction of Chemotherapy Resistance in Preclinical Models of Ovarian Cancer by Positron Emission Tomography. - 2019
Measurement of Tumor Antioxidant Capacity and Prediction of Chemotherapy Resistance in Preclinical Models of Ovarian Cancer by Positron Emission Tomography.
Greenwood, Hannah E; McCormick, Patrick N; Gendron, Thibaultet al.
2019 • In Clinical Cancer Research, 25 (8), p. 2471 - 2482
Biomarkers; Radiopharmaceuticals; Cystine/metabolism; Drug Resistance, Neoplasm; Positron-Emission Tomography/methods; Positron-Emission Tomography; Oncology; Cancer Research
Abstract :
[en] ("[en] 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 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 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.
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 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.","[en] ","")
Disciplines :
Chemistry Oncology Radiology, nuclear medicine & imaging
Author, co-author :
Greenwood, Hannah E; Centre for Advanced Biomedical Imaging, Division of Medicine, University College London, London, United Kingdom
McCormick, Patrick N; Centre for Advanced Biomedical Imaging, Division of Medicine, University College London, London, United Kingdom
Gendron, Thibault ; Université de Liège - ULiège > Département de chimie (sciences) > Chimie organique-nucléaire ; Department of Chemistry, Institute of Nuclear Medicine, University College London, London, United Kingdom
Glaser, Matthias; Department of Chemistry, Institute of Nuclear Medicine, University College London, London, United Kingdom
Pereira, Raul; Centre for Advanced Biomedical Imaging, Division of Medicine, University College London, London, United Kingdom
Maddocks, Oliver D K ; Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
Sander, Kerstin; Department of Chemistry, Institute of Nuclear Medicine, University College London, London, United Kingdom
Zhang, Tong; Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
Koglin, Norman; Life Molecular Imaging GmbH, Berlin, Germany
Lythgoe, Mark F; Centre for Advanced Biomedical Imaging, Division of Medicine, University College London, London, United Kingdom
Årstad, Erik ; Department of Chemistry, Institute of Nuclear Medicine, University College London, London, United Kingdom
Hochhauser, Daniel; Cancer Research UK Drug-DNA Interactions Research Group, UCL Cancer Institute, University College London, London, United Kingdom
Witney, Timothy H ; Centre for Advanced Biomedical Imaging, Division of Medicine, University College London, London, United Kingdom. tim.witney@kcl.ac.uk
Measurement of Tumor Antioxidant Capacity and Prediction of Chemotherapy Resistance in Preclinical Models of Ovarian Cancer by Positron Emission Tomography.
Publication date :
15 April 2019
Journal title :
Clinical Cancer Research
ISSN :
1078-0432
eISSN :
1557-3265
Publisher :
American Association for Cancer Research Inc., United States
Wellcome Trust UCL - University College London Royal Society
Funding text :
D. Hochhauser reports receiving commercial research grants from Merck Serono. N. Koglin holds ownership interest (including patents) in FSPG. T.H. Witney reports receiving commercial research grants from Life Molecular Imaging GmbH, and is a consultant/advisory board member for CellSight Technologies, Inc. No potential conflicts of interest were disclosed by the other authors.The authors would like to thank Stephen Patrick, May Zaw-Thin, and Andrew Stephens for insightful scientific discussions and William Day for help with flow cytometric experiments. This study was funded through a Wellcome Trust and Royal Society Sir Henry Dale Fellowship (107610/ Z/15/Z) and the Cancer Research UK-UCL Centre Development Award (C416/A18088) to Timothy Witney, the CRUK & EPSRC Comprehensive Cancer Imaging Centre at KCL & UCL (C1519/A16463) to Erik Årstad, and financial support from Life Molecular Imaging GmbH (formerly Piramal Imaging) to Timothy Witney. UCL radiochemistry is funded in-part by the Department of Health's NIHR Biomedical Research Centres funding scheme. Oliver Maddocks and Tong Zhang are supported by CRUK Career Development Fellowship C53309/A19702. Royal Society Sir Henry Dale Fellowship; Cancer Research UK-UCL Centre Development Award
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