Assessment of Tumor Redox Status Through ()-4-(3-[F]fluoropropyl)-L-Glutamic Acid PET Imaging of System X Activity

Overview

Journal Cancer Res

Specialty Oncology

Date 2018 Nov 8

PMID 30401715

Citations 31

Authors

Patrick N McCormick

Hannah E Greenwood

Matthias Glaser

Oliver D K Maddocks

Thibault Gendron

Kerstin Sander

Gayatri Gowrishankar

Aileen Hoehne

Tong Zhang

Adam J Shuhendler

David Y Lewis

Mathias Berndt

Norman Koglin

Mark F Lythgoe

Sanjiv S Gambhir

Erik Arstad

Timothy H Witney

Affiliations

Soon will be listed here.

Abstract

The cell's endogenous antioxidant system is vital to maintenance of redox homeostasis. Despite its central role in normal and pathophysiology, no noninvasive tools exist to measure this system in patients. The cystine/glutamate antiporter system x maintains the balance between intracellular reactive oxygen species and antioxidant production through the provision of cystine, a key precursor in glutathione biosynthesis. Here, we show that tumor cell retention of a system x -specific PET radiotracer, ()-4-(3-[F]fluoropropyl)-L-glutamic acid ([F]FSPG), decreases in proportion to levels of oxidative stress following treatment with a range of redox-active compounds. The decrease in [F]FSPG retention correlated with a depletion of intracellular cystine resulting from increased glutathione biosynthesis, shown through [U-C, U-N]cystine isotopic tracing. , treatment with the chemotherapeutic doxorubicin decreased [F]FSPG tumor uptake in a mouse model of ovarian cancer, coinciding with markers of oxidative stress but preceding tumor shrinkage and decreased glucose utilization. Having already been used in pilot clinical trials, [F]FSPG PET could be rapidly translated to the clinic as an early redox indicator of tumor response to treatment. SIGNIFICANCE: [F]FSPG PET imaging provides a sensitive noninvasive measure of tumor redox status and provides an early marker of tumor response to therapy..

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