TBIO-14. CHARACTERISATION OF THE ARGININE PATHWAY ENZYMES IN PAEDIATRIC BRAIN TUMOURS TO DETERMINE SUSCEPTIBILITY TO THERAPEUTIC ARGININE DEPLETION

INTRODUCTION: Extracellular arginine dependency (auxotrophy) is increasingly being recognised in several tumours. This 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 is known to exhibit this, the expression of the arginine pathway enzymes has not been delineated in paediatric brain tumours. METHODS: We used immunohistochemical methods to stain for arginine pathway enzymes in Paediatric High grade glioma (pHGG), low grade glioma (pLGG) and medulloblastoma (MB) tumour tissue microarrays (TMAs). The antibodies detected protein expression of the metaboliser Arginase (Arg2), recycling enzymes ornithine transcarbamoylase (OTC), Arginosuccinate synthetase (ASS1) and arginosuccinate lyase (ASL) as well as the transporter SLC7A1. RESULTS: Deficiency of OTC, ASS1 and ASL were seen in 92%, 98% and 93% of pHGG samples (n=156) respectively, with deficiency defined as low (<20%) or negative antibody expression. Identical results were seen in pLGG (n=98) - 83%, 97% and 95% were deficient in OTC, ASS1 and ASL. Both pHGG and pLGG highly expressed SLC7A1 and Arg2, demonstrating that they could transport and utilise arginine. In MB (n=82), this auxotrophic signature was again seen in 90% of TMAs with absent or low expression of OTC, ASS1 and ASL and high Arg2 and SLC7A1 expression. CONCLUSIONS: These results show that pHGG, pLGG and MB are arginine auxotrophs. 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 MB and pLGG.