TB-12 arginine auxotrophy in paediatric CNS tumours: the rationale for therapeutic arginine depletion as a novel anti-cancer therapy

BACKGROUND: Despite significant improvements in survival of children with cancer, certain brain tumours have poor outcomes, particularly in the relapse setting. Therefore novel therapeutic strategies are needed. We have identified that some cancers are dependent on arginine for survival due to the absence of arginine recycling enzymes (arginine auxotrophism) and that this arginine addiction can be targeted. There is no published data thus far on arginine auxotrophy in paediatric CNS tumours.

AIM: To examine the levels of gene expression of key enzymes involved in the synthesis and recycling of arginine in CNS tumours.

METHODS: Using the R2 genomics platform, we analysed the expression of arginoscuccinate synthetase 1 (ASS1); ornithine transcarbamylase (OTC); arginosuccinate lyase (ASL), Arginase 1 and 2 isoforms and the cationic transporters CAT1 and CAT2 in a range of published CNS tumour datasets. Arginine auxotrophy was defined normal or high expression of ASS and low expression of OTC, compared to normal brain tissue and the housekeeping gene GAPDH.

RESULTS: High grade glioma, diffuse intrinsic pontine glioma, ependymoma and medulloblastoma had high ASS and very low OTC expression levels compared to normal brain - strongly suggesting arginine auxotrophism. Interesting all CNS tumours studied had high ASL expression.

CONCLUSION: Several difficult to treat CNS tumours have the molecular features of arginine dependence. Therapeutic arginine depletion (using recombinant arginase BCT-100) may be a novel strategy for treatment of these tumours within the context of an early phase clinical trial.