Biology subjects

Barber, A. R.

Publications and source records attributed to Barber, A. R..

3 recordsLinked to original sources

bioRxiv2026

System xc- imaging maps ferroptosis-linked redox remodeling in cancer

Ferroptosis is a regulated non-apoptotic form of programmed cell death that is implicated in tumor suppression and the normal tissue damage response. While the link between redox stress and ferroptosis is well established, no non-invasive methods exist to assess ferroptosis in vivo. Here, we demonstrate that the redox-sensitive positron emission tomography radiotracer and system xc-substrate, 18F-(S)-4-(3-fluoropropyl)-L-glutamic acid ([18F]FSPG), serves as a non-invasive marker of tumor ferroptosis. Global changes in amino acids, glutathione, and system xc- activity occurred before loss of membrane integrity in cells sensitive to ferroptosis, but not in resistant cells. Resistant cells sensitized to ferroptosis through nuclear factor erythroid 2-related factor 2 (NRF2) knockout had reduced glutathione and [18F]FSPG retention, which were rescued by ferroptosis inhibitors. In vivo, immune checkpoint blockade decreased ferroptosis-specific [18F]FSPG tumor retention prior to immune cell infiltration. Together, our data demonstrate that [18F]FSPG can identify early redox changes that precede ferroptosis and enabled real-time monitoring of immunotherapeutic efficacy.

cancer biology↗

bioRxiv2023

Imaging the master regulator of the antioxidant response in non-small cell lung cancer with positron emission tomography

Mutations in the NRF2-KEAP1 pathway are common in non-small cell lung cancer (NSCLC) and confer broad-spectrum therapeutic resistance, leading to poor outcomes. The cystine/glutamate antiporter, system xc-, is one of the >200 cytoprotective proteins controlled by NRF2, which can be non-invasively imaged by (S)-4-(3-18F-fluoropropyl)--glutamate ([18F]FSPG) positron emission tomography (PET). Through genetic and pharmacologic manipulation, we show that [18F]FSPG provides a sensitive and specific marker of NRF2 activation in advanced preclinical models of NSCLC. We validate imaging readouts with metabolomic measurements of system xc- activity and their coupling to intracellular glutathione concentration. A redox gene signature was measured in patients from the TRACERx 421 cohort, suggesting an opportunity for patient stratification prior to imaging. Furthermore, we reveal that system xc- is a metabolic vulnerability that can be therapeutically targeted for sustained tumour growth suppression in aggressive NSCLC. Our results establish [18F]FSPG as predictive marker of therapy resistance in NSCLC and provide the basis for the clinical evaluation of both imaging and therapeutic agents that target this important antioxidant pathway.

cancer biology↗

bioRxiv2022

mRNA therapy restores ureagenesis and corrects glutathione metabolism in argininosuccinic aciduria

Argininosuccinate lyase (ASL) is a key enzyme integral to the hepatic urea cycle which is required for ammonia detoxification, and the citrulline-nitric oxide (NO) cycle for NO production. ASL deficient patients present with argininosuccinic aciduria (ASA), an inherited metabolic disease with hyperammonaemia and a chronic systemic phenotype with neurocognitive impairment and chronic liver disease. ASL deficiency as an inherited model of systemic NO deficiency, shows enhanced nitrosative and oxidative stress. Here, we describe the dysregulation of glutathione biosynthesis and upstream cysteine utilization in ASL-deficient patients and mice using targeted metabolomics and in vivo positron emission tomography (PET) imaging using (S)-4-(3-18F-fluoropropyl)-L-glutamate ([18F]FSPG). Upregulation of cysteine metabolism contrasted with glutathione depletion and down-regulated antioxidant pathways. hASL mRNA encapsulated in lipid nanoparticles corrected and rescued the neonatal and adult Asl-deficient mouse phenotypes, respectively, enhancing ureagenesis and glutathione metabolism and ameliorating chronic liver disease. We further present [18F]FSPG PET as a novel non-invasive diagnostic tool to assess liver disease and therapeutic efficacy in ASA. These findings support clinical translation of mRNA therapy for ASA.

genetics↗