2025
J Exp Clin Cancer Res. 2025 Aug 14;44(1):239. doi: 10.1186/s13046-025-03502-8.
Arginine depletion potentiates standard-of-care chemo-immunotherapy in preclinical models of high-risk neuroblastoma
Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia. School of Clinical Medicine, Faculty of Medicine & Health, UNSW Sydney, Sydney, Australia. Kids Cancer Centre, Sydney Children's Hospital, Randwick, Australia. Birmingham Children's Hospital, University of Birmingham, Birmingham, UK. Bio-cancer Treatment International Ltd, Shatin, New Territories, Hong Kong. University of New South Wales Centre for Childhood Cancer Research, UNSW Sydney, Sydney, NSW, Australia. Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia. School of Clinical Medicine, Faculty of Medicine & Health, UNSW Sydney, Sydney, Australia. Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia. School of Clinical Medicine, Faculty of Medicine & Health, UNSW Sydney, Sydney, Australia. Contributed equally.
Service type: Stock strains
Abstract
Background: Dysregulated amino acid metabolism creates cancer-specific vulnerabilities. Neuroblastoma tumors have dysregulated arginine metabolism that renders them sensitive to systemic arginine deprivation. Arginase therapy has been proposed as a therapeutic approach for neuroblastoma treatment and has a favorable safety profile in pediatric cancer patients, however optimal therapeutic combinations remain unexplored.
Methods: The anti-tumor effects of BCT-100, a pegylated human arginase, were studied in neuroblastoma cell models by metabolite profiling, proteomics, and viability, clonogenicity, and protein translation assays. BCT-100 efficacy was assessed in the Th-MYCN transgenic neuroblastoma mouse model and in neuroblastoma cell line and patient-derived xenograft models.
Results: In vitro, depletion of arginine by BCT-100 arrested protein translation and cellular proliferation, with effects on clonogenicity enhanced in combination with standard-of-care chemotherapeutics SN-38/temozolomide and mafosfamide/topotecan. In vivo, BCT-100 treatment spared liver arginine while significantly depleting plasma and tumor arginine in Th-MYCN mice, and extended tumor latency (> 100 vs. 45.5 days) in mice pre-emptively treated at weaning. In mice with established tumors, BCT-100 prolonged tumor progression delay when combined with standard-of-care chemo- (> 90 vs. 25 days) or chemo-immuno-therapy (49.5 vs. 35.5 days). Tumor progression delay was also observed in cell line and patient-derived xenografts with BCT-100 treatment, including relapsed/refractory disease models. No increased toxicity was observed with the addition of BCT-100 to established therapies.
Conclusions: The arginase BCT-100 profoundly disrupts neuroblastoma growth in vitro and in vivo, an effect enhanced in combination with standard-of-care chemo-immuno-therapy. Our data supports further assessment of arginine-depleting combination therapies as a new treatment strategy for neuroblastoma.
Keywords: Arginase; Arginine; Metabolism; Neuroblastoma; Patient-derived xenografts; Preclinical testing.
