背景:胰腺导管腺癌(PDAC)是一种侵袭性疾病,除了首次挽救治疗外,没有有意义的治疗选择。通过氨基酸限制靶向PDAC代谢已成为一种有前途的新策略。用天冬酰胺酶,消耗血浆谷氨酰胺和天冬酰胺的酶,达到临床试验。在这项研究中,我们研究了单独使用天冬酰胺酶制剂Pegcrisantaspase(PegC)以及与标准化疗药物联合使用的抗PDAC活性.
方法:使用小鼠和人PDAC细胞系,我们评估了PegC对细胞增殖的影响,细胞死亡,和细胞周期进程。我们进一步表征了PegC对蛋白质合成的体外作用以及活性氧的产生和谷胱甘肽的水平。一种主要的细胞抗氧化剂。另外的细胞系研究检查了PegC与标准护理化学治疗剂的组合的效果。在体内,PegC的耐受性和疗效,以及对血浆氨基酸水平的影响,使用C57BL/6衍生的KPC同基因小鼠模型进行评估。
结果:在这里,我们报道了PegC在一组人和鼠PDAC细胞系中显示出有效的抗增殖活性。增殖的减少伴随着蛋白质合成的抑制和谷胱甘肽水平的降低。在体内,PegC可耐受并有效降低血浆谷氨酰胺和天冬酰胺水平,在PDAC的同基因小鼠模型中导致肿瘤生长的统计学显著抑制。将PegC与标准的化疗药物联合使用没有可观察到的体外或体内益处,包括奥沙利铂,伊立替康,5-氟尿嘧啶,紫杉醇,和吉西他滨.值得注意的是,PegC处理增加了天冬酰胺和丝氨酸生物合成酶的肿瘤表达。
结论:综合来看,我们的结果证明了PegC在PDAC中的潜在治疗用途,并强调了确定可改善细胞毒性和/或减少耐药途径诱导的联合治疗方案的候选药物的重要性.
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease without meaningful therapeutic options beyond the first salvage therapy. Targeting PDAC metabolism through amino acid restriction has emerged as a promising new strategy, with asparaginases, enzymes that deplete plasma glutamine and asparagine, reaching clinical trials. In this study, we investigated the anti-PDAC activity of the
asparaginase formulation Pegcrisantaspase (PegC) alone and in combination with standard-of-care chemotherapeutics.
METHODS: Using mouse and human PDAC cell lines, we assessed the impact of PegC on cell proliferation, cell death, and cell cycle progression. We further characterized the in vitro effect of PegC on protein synthesis as well as the generation of reactive oxygen species and levels of glutathione, a major cellular antioxidant. Additional cell line studies examined the effect of the combination of PegC with standard-of-care chemotherapeutics. In vivo, the tolerability and efficacy of PegC, as well as the impact on plasma amino acid levels, was assessed using the C57BL/6-derived KPC syngeneic mouse model.
RESULTS: Here we report that PegC demonstrated potent anti-proliferative activity in a panel of human and murine PDAC cell lines. This decrease in proliferation was accompanied by inhibited protein synthesis and decreased levels of glutathione. In vivo, PegC was tolerable and effectively reduced plasma levels of glutamine and asparagine, leading to a statistically significant inhibition of tumor growth in a syngeneic mouse model of PDAC. There was no observable in vitro or in vivo benefit to combining PegC with standard-of-care chemotherapeutics, including oxaliplatin, irinotecan, 5-fluorouracil, paclitaxel, and gemcitabine. Notably, PegC treatment increased tumor expression of asparagine and serine biosynthetic enzymes.
CONCLUSIONS: Taken together, our results demonstrate the potential therapeutic use of PegC in PDAC and highlight the importance of identifying candidates for combination regimens that could improve cytotoxicity and/or reduce the induction of resistance pathways.