Targeting PDGFRα-activated glioblastoma through specific inhibition of SHP-2-mediated signaling
Targeting PDGFRα-activated glioblastoma through specific inhibition of SHP-2-mediated signaling
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通过特异性抑制 SHP-2 介导的信号传导靶向 PDGFR α 激活的胶质母细胞瘤
DOI：
10.1093/neuonc/noz107
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发表时间：
2019-11-01
期刊：
影响因子：
15.9
通讯作者：
Feng, Haizhong
中科院分区：
文献类型：
--
作者：
Sang, Youzhou;Hou, Yanli;Feng, Haizhong
背景胶质母细胞瘤（GBM）是最恶性的原发性脑肿瘤，中位生存率低。GBM的治疗特别具有挑战性，因为它对化疗具有内在抗性，并且由于血脑屏障，药物难以到达肿瘤床。在这里，我们检查了SHP 099的功效，SHP 099是一种有效的、选择性的和口服的SHP-2抑制剂，用于治疗具有活化的血小板衍生生长因子受体α（PDGFR α）信号传导的GBM。评价了SHP 099对神经祖细胞（NPC）、GBM细胞系和患者源性胶质瘤干细胞样细胞（GSC）细胞存活的影响。评估了SHP 099的脑和血浆药代动力学及其抑制SHP-2信号传导的能力。使用转化的小鼠星形胶质细胞和GSC原位异种移植模型评估了SHP 099单药或与替莫唑胺（TMZ）联合给药的疗效。与NPC相比，在体外和体内，SHP 099通过靶向SHP-2刺激GBM中细胞外信号调节蛋白激酶1和2的活化，显著抑制了已建立的GBM细胞、GSC和转化小鼠星形胶质细胞中活化的PDGFR α信号传导。SHP 099处理特异性抑制JUN（PDGFR信号传导的下游效应子）的表达，从而减弱具有活化PDGFR α的GBM细胞的细胞周期进展。此外，SHP 099在脑中以有效浓度蓄积，并有效抑制原位GBM肿瘤异种移植物生长。SHP 099单药或与TMZ联合给药均表现出抗肿瘤活性，并为携带GBM肿瘤异种移植物的动物提供了显著的生存获益。我们的数据证明了SHP 099作为改善GBM联合TMZ临床治疗的潜在治疗选择的实用性和可行性。
Background. Glioblastoma (GBM) is the most malignant primary brain tumor, with dismal median survival. Treatment of GBM is particularly challenging given the intrinsic resistance to chemotherapy and difficulty of drugs to reach the tumor beds due to the blood-brain barrier. Here, we examined the efficacy of SHP099, a potent, selective, and oral SHP-2 inhibitor for treating GBM with activated platelet derived growth factor receptor alpha (PDGFR alpha) signaling.Methods. The effects of SHP099 on cell survival of neural progenitor cells (NPCs), GBM cell lines, and patient-derived glioma stem-like cells (GSCs) were evaluated. Brain and plasma pharmacokinetics of SHP099 and its ability to inhibit SHP-2 signaling were assessed. SHP099 efficacy as a single agent or in combination with temozolomide (TMZ) was assessed using transformed mouse astrocyte and GSC orthotopic xenograft models.Results. Activated PDGFR alpha signaling in established GBM cells, GSCs, and transformed mouse astrocytes was significantly inhibited by SHP099 compared with NPCs in vitro and in vivo through targeting SHP-2-stimulated activation of extracellular signal-regulated protein kinases 1 and 2 in GBM. SHP099 treatment specifically inhibited expression of JUN, a downstream effector of PDGFR signaling, thereby attenuating cell cycle progression in GBM cells with activated PDGFR alpha. Moreover, SHP099 accumulated at efficacious concentrations in the brain and effectively inhibited orthotopic GBM tumor xenograft growth. SHP099 exhibited antitumor activity either as a single agent or in combination with TMZ and provided significant survival benefits for GBM tumor xenograft-bearing animals.Conclusions. Our data demonstrate the utility and feasibility of SHP099 as a potential therapeutic option for improving the clinical treatment of GBM in combination with TMZ.