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Characterisation of Expression the Arginine Pathway Enzymes in Childhood Brain Tumours to Determine Susceptibility to Therapeutic Arginine Depletion

Bishop, Eleanor; Dimitrova, Monika; Froggatt, Alexander; Estevez-Cebrero, Maria; Storer, Lisa C. D.; Mussai, Francis; Paine, Simon; Grundy, Richard G.; Dandapani, Madhumita

Authors

Eleanor Bishop

Monika Dimitrova

Alexander Froggatt

Maria Estevez-Cebrero

Lisa C. D. Storer

Francis Mussai

Simon Paine

RICHARD GRUNDY richard.grundy@nottingham.ac.uk
Professor of Paediatric Neuro-Oncology

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Dr MADHUMITA DANDAPANI Madhumita.Dandapani@nottingham.ac.uk
Clinical Associate Professor of Paediatric Oncology/Neuro Oncology



Contributors

Flavia Prodam
Editor

Abstract

Despite significant improvements in treatment and survival in paediatric cancers, outcomes for children with brain tumours remain poor. Novel therapeutic approaches are needed to improve survival and quality of survival. Extracellular arginine dependency (auxotrophy) has been recognised in several tumours as a potential therapeutic target. This dependency is due to the inability of cancer cells to recycle or synthesise intracellular arginine through the urea cycle pathway compared to normal cells. Whilst adult glioblastoma exhibits this dependency, the expression of the arginine pathway enzymes has not been delineated in paediatric brain tumours. We used immunohistochemical (IHC) methods to stain for arginine pathway enzymes in paediatric high-grade glioma (pHGG), low-grade glioma (pLGG), ependymoma (EPN), and medulloblastoma (MB) tumour tissue microarrays (TMAs). The antibodies detected protein expression of the metaboliser arginase (Arg1 and Arg2); recycling enzymes ornithine transcarbamoylase (OTC), argininosuccinate synthetase (ASS1), and argininosuccinate lyase (ASL); and the transporter SLC7A1. Deficiency of OTC, ASS1, and ASL was seen in 87.5%, 94%, and 79% of pHGG samples, respectively, consistent with an auxotrophic signature. Similar result was obtained in pLGG with 96%, 93%, and 91% of tumours being deficient in ASL, ASS1, and OTC, respectively. 79%, 88%, and 85% of MB cases were ASL, ASS1, and OTC deficient whilst ASL and OTC were deficient in 57% and 91% of EPN samples. All tumour types highly expressed SLC7A1 and Arginase, with Arg2 being the main isoform, demonstrating that they could transport and utilise arginine. Our results show that pHGG, pLGG, EPN, and MB demonstrate arginine auxotrophy based on protein expression and are likely to be susceptible to arginine depletion. Pegylated arginase (BCT-100) is currently in phase I/II trials in relapsed pHGG. Our results suggest that therapeutic arginine depletion may also be useful in other tumour types and IHC analysis of patient tumour samples could help identify patients likely to benefit from this treatment.

Citation

Bishop, E., Dimitrova, M., Froggatt, A., Estevez-Cebrero, M., Storer, L. C. D., Mussai, F., …Dandapani, M. (2022). Characterisation of Expression the Arginine Pathway Enzymes in Childhood Brain Tumours to Determine Susceptibility to Therapeutic Arginine Depletion. BioMed Research International, 2022, Article 9008685. https://doi.org/10.1155/2022/9008685

Journal Article Type Article
Acceptance Date May 19, 2022
Online Publication Date Jun 22, 2022
Publication Date Jun 22, 2022
Deposit Date Jul 4, 2022
Publicly Available Date Jul 5, 2022
Journal BioMed Research International
Print ISSN 2314-6133
Electronic ISSN 2314-6141
Publisher Hindawi Publishing Corporation
Peer Reviewed Peer Reviewed
Volume 2022
Article Number 9008685
DOI https://doi.org/10.1155/2022/9008685
Keywords General Immunology and Microbiology; General Biochemistry, Genetics and Molecular Biology; General Medicine
Public URL https://nottingham-repository.worktribe.com/output/8636707
Publisher URL https://www.hindawi.com/journals/bmri/2022/9008685/

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