Department of Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland.
Johns Hopkins Drug Discovery, Johns Hopkins School of Medicine, Baltimore, Maryland.
Mol Cancer Ther. 2020 Feb;19(2):397-408. doi: 10.1158/1535-7163.MCT-19-0319. Epub 2019 Oct 8.
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. , 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.
谷氨酰胺的碳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）的治疗潜力尚未完全了解，MPNST 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 的谷氨酰胺依赖性，JHU395 是一种新型口服生物利用的 GA 前药，旨在在血浆中循环时保持惰性，但在靶组织中渗透并释放活性 GA。与源自健康周围神经的施万细胞相比，人 MPNST 细胞对谷氨酰胺剥夺和 GA 剂量依赖性生长抑制均具有选择性易感性。口服 JHU395 可将活性 GA 递送至肿瘤，肿瘤与血浆的暴露比超过 2 倍，并且在没有观察到毒性的情况下显著抑制了鼠侧腹 MPNST 模型中的肿瘤生长。肿瘤中的全局代谢组学研究和稳定同位素标记通量分析确定了受影响的多种谷氨酰胺依赖性代谢物，包括对嘌呤合成的显著影响。这些数据表明，谷氨酰胺拮抗作用是 MPNST 的一种潜在的抗肿瘤策略。
