Kimberley M Hanssen, Jayne Murray, Ruby Pandher, Stephanie Alfred, Laura D Gamble, Jennifer Brand, Erin Mosmann, Frances K Kusuma, Crystal Mak, Adam Kearns, Alvin Kamili, Caroline Atkinson, Alexis Z Minchaca, Jean Bertoldo, David S Ziegler, Francis Mussai, Paul N M Cheng, Murray D Norris, Jamie I Fletcher, Michelle Haber
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引用次数: 0
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.
背景:失调的氨基酸代谢产生癌症特异性脆弱性。神经母细胞瘤肿瘤有失调的精氨酸代谢,使它们对全身精氨酸剥夺敏感。精氨酸酶治疗已被提议作为神经母细胞瘤治疗的一种治疗方法,并且在儿童癌症患者中具有良好的安全性,然而最佳的治疗组合仍未探索。方法:在神经母细胞瘤细胞模型中,通过代谢物谱分析、蛋白质组学、活力、克隆原性和蛋白质翻译试验研究聚乙二醇化人精氨酸酶BCT-100的抗肿瘤作用。在Th-MYCN转基因神经母细胞瘤小鼠模型、神经母细胞瘤细胞系和患者来源的异种移植物模型中评估BCT-100的疗效。结果:在体外,BCT-100消耗精氨酸抑制了蛋白质翻译和细胞增殖,与标准化疗药物cn -38/替莫唑胺和mafosfamide/拓扑替康联合使用时,对克隆原性的影响增强。在体内,BCT-100治疗在显著消耗Th-MYCN小鼠血浆和肿瘤精氨酸的同时,保留了肝脏精氨酸,并延长了断奶时预先治疗小鼠的肿瘤潜伏期(bb100对45.5天)。在已建立肿瘤的小鼠中,BCT-100与标准治疗化疗(bbb90 vs. 25天)或化疗免疫治疗(49.5 vs. 35.5天)联合使用可延长肿瘤进展延迟。在接受BCT-100治疗的细胞系和患者来源的异种移植物中,包括复发/难治性疾病模型,也观察到肿瘤进展延迟。在已建立的治疗方法中添加BCT-100未观察到毒性增加。结论:精氨酸酶BCT-100在体外和体内严重破坏神经母细胞瘤的生长,与标准治疗的化学免疫治疗相结合,效果增强。我们的数据支持进一步评估精氨酸消耗联合疗法作为神经母细胞瘤的新治疗策略。
期刊介绍:
The Journal of Experimental & Clinical Cancer Research is an esteemed peer-reviewed publication that focuses on cancer research, encompassing everything from fundamental discoveries to practical applications.
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