Arginine auxotrophic gene signature in paediatric sarcomas and brain tumours provides a viable target for arginine depletion therapies

// Ashley Vardon 1, * , Madhumita Dandapani 1, * , Daryl Cheng 1, * , Paul Cheng 2 , Carmela De Santo 1 and Francis Mussai 1 1 Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom 2 Bio-Cancer Treatment International Ltd, Hong Kong, China * These authors have contributed equally to this work Correspondence to: Francis Mussai, email: Francis.mussai@bch.nhs.uk Keywords: paediatric, sarcomas, brain, arginine, auxotrophism Received: October 22, 2016 Accepted: June 05, 2017 Published: June 29, 2017 ABSTRACT Paediatric sarcomas and brain tumours, remain cancers of significant unmet need, with a poor prognosis for patients with high risk disease or those who relapse, and significant morbidities from treatment for those that survive using standard treatment approaches. Novel treatment strategies, based on the underlying tumour biology, are needed to improve outcomes. Arginine is a semi-essential amino acid that is imported from the extracellular microenvironment or recycled from intracellular precursors through the combined expression of the enzymes ornithine transcarbamylase (OTC), argininosuccinate synthase (ASS) and argininosuccinate lyase (ASL) enzymes. The failure to express at least one of these recycling enzymes makes cells reliant on extracellular arginine – a state known as arginine auxotrophism. Here we show in large in silico patient cohorts that paediatric sarcomas and brain tumours express predominately the arginine transporter SLC7A1 and the arginine metabolising enzyme Arginase 2 (ARG2), but have low-absent expression of OTC. The arginine metabolic pathway correlated with the expression of genes associated with tumour pathogenesis, and overall survival in paediatric sarcomas. This gene signature of arginine auxotrophism indicates paediatric sarcomas and brain tumours are a viable target for therapeutic arginase drugs under current clinical trial development.