谷氨酰胺拮抗剂前药JHU - 083可减缓恶性胶质瘤的生长并破坏mTOR信号传导。 - Suppr

The glutamine antagonist prodrug JHU-083 slows malignant glioma growth and disrupts mTOR signaling.

作者信息

Yamashita Alex Shimura, da Costa Rosa Marina, Stumpo Vittorio, Rais Rana, Slusher Barbara S, Riggins Gregory J

机构信息

Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Johns Hopkins Drug Discovery, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

出版信息

Neurooncol Adv. 2020 Oct 29;3(1):vdaa149. doi: 10.1093/noajnl/vdaa149. eCollection 2021 Jan-Dec.

BACKGROUND

Metabolic reprogramming is a common feature in cancer, and it is critical to facilitate cancer cell growth. and mutations (mut) are the most common genetic alteration in glioma grade II and III and secondary glioblastoma and these mutations increase reliance on glutamine metabolism, suggesting a potential vulnerability. In this study, we tested the hypothesis that the brain penetrant glutamine antagonist prodrug JHU-083 reduces glioma cell growth.

MATERIAL AND METHODS

We performed cell growth, cell cycle, and protein expression in glutamine deprived or () gene silenced glioma cells. We tested the effect of JHU-083 on cell proliferation, metabolism, and mTOR signaling in cancer cell lines. An orthotopic glioma model was used to test the efficacy of JHU-083 in vivo.

RESULTS

Glutamine deprivation and gene silencing reduced glioma cell proliferation in vitro in glioma cells. JHU-083 reduced glioma cell growth in vitro, modulated cell metabolism, and disrupted mTOR signaling and downregulated Cyclin D1 protein expression, through a mechanism independent of TSC2 modulation and glutaminolysis. IDH1R132H isogenic cells preferentially reduced cell growth and mTOR signaling downregulation. In addition, guanine supplementation partially rescued mut glioma cell growth, mTOR signaling, and Cyclin D1 protein expression in vitro. Finally, JHU-083 extended survival in an intracranial mut glioma model and reduced intracranial pS6 protein expression.

CONCLUSION

Targeting glutamine metabolism with JHU-083 showed efficacy in preclinical models of mut glioma and measurably decreased mTOR signaling.

背景

代谢重编程是癌症的一个常见特征，对促进癌细胞生长至关重要。异柠檬酸脱氢酶1（IDH1）和异柠檬酸脱氢酶2（IDH2）突变是二级和三级胶质瘤以及继发性胶质母细胞瘤中最常见的基因改变，这些突变增加了对谷氨酰胺代谢的依赖，提示潜在的脆弱性。在本研究中，我们检验了脑渗透性谷氨酰胺拮抗剂前药JHU - 083可降低胶质瘤细胞生长的假说。

材料与方法

我们在谷氨酰胺缺乏或IDH1基因沉默的胶质瘤细胞中进行了细胞生长、细胞周期和蛋白质表达实验。我们测试了JHU - 083对癌细胞系中细胞增殖、代谢和mTOR信号传导的影响。使用原位IDH1R132H胶质瘤模型在体内测试JHU - 083的疗效。

结果

谷氨酰胺缺乏和IDH1基因沉默在体外降低了胶质瘤细胞的增殖。JHU - 083在体外降低了胶质瘤细胞的生长，调节了细胞代谢，破坏了mTOR信号传导并下调了细胞周期蛋白D1的蛋白质表达，其机制独立于结节性硬化复合物2（TSC2）调节和谷氨酰胺分解。IDH1R132H同基因细胞优先降低细胞生长和mTOR信号传导下调。此外，鸟嘌呤补充在体外部分挽救了IDH1R132H突变的胶质瘤细胞生长、mTOR信号传导和细胞周期蛋白D1的蛋白质表达。最后，JHU - 083延长了颅内IDH1R132H突变胶质瘤模型的生存期并降低了颅内磷酸化核糖体蛋白S（pS6）的蛋白质表达。