The carbon and nitrogen components of glutamine are used for multiple biosynthetic processes by tumors. Glutamine metabolism and the therapeutic potential of glutamine antagonists (GA), however, are incompletely understood in malignant peripheral nerve sheath tumor (MPNST), an aggressive soft tissue sarcoma observed in patients with neurofibromatosis type I. We investigated glutamine dependence of MPNST using JHU395, a novel orally bioavailable GA prodrug designed to circulate inert in plasma, but permeate and release active GA within target tissues. Human MPNST cells, compared with Schwann cells derived from healthy peripheral nerve, were selectively susceptible to both glutamine deprivation and GA dose-dependent growth inhibition. In vivo, orally administered JHU395 delivered active GA to tumors with over 2-fold higher tumor-to-plasma exposure, and significantly inhibited tumor growth in a murine flank MPNST model without observed toxicity. Global metabolomics studies and stable isotope–labeled flux analyses in tumors identified multiple glutamine-dependent metabolites affected, including prominent effects on purine synthesis. These data demonstrate that glutamine antagonism is a potential antitumor strategy for MPNST.

中文翻译：

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新型谷氨酰胺拮抗剂前药JHU395对恶性周围神经鞘瘤具有抗肿瘤活性

谷氨酰胺的碳和氮成分被肿瘤用于多种生物合成过程。然而，在恶性外周神经鞘瘤 (MPNST) 中，谷氨酰胺代谢和谷氨酰胺拮抗剂 (GA) 的治疗潜力尚不完全清楚，这是一种在 I 型神经纤维瘤病患者中观察到的侵袭性软组织肉瘤。我们使用 JHU395 研究了 MPNST 对谷氨酰胺的依赖性，一种新型口服生物可利用 GA 前药，旨在在血浆中惰性循环，但在靶组织内渗透和释放活性 GA。与源自健康外周神经的雪旺氏细胞相比，人类 MPNST 细胞对谷氨酰胺剥夺和 GA 剂量依赖性生长抑制选择性敏感。在体内，口服 JHU395 向肿瘤递送活性 GA，肿瘤与血浆的暴露量高出 2 倍以上，并且显着抑制了小鼠侧腹 MPNST 模型中的肿瘤生长，而没有观察到毒性。全球代谢组学研究和肿瘤中稳定同位素标记的通量分析确定了多种谷氨酰胺依赖性代谢物受到影响，包括对嘌呤合成的显着影响。这些数据表明，谷氨酰胺拮抗作用是 MPNST 的潜在抗肿瘤策略。