Inhibiting 4EBP1 in Glioblastoma.
Inhibiting 4EBP1 in Glioblastoma.
复制标题
DOI：
10.1158/1078-0432.ccr-17-0042
复制
发表时间：
2018-01-01
期刊：
影响因子：
--
通讯作者：
Weiss WA
中科院分区：
文献类型：
--
作者：
Fan QW;Nicolaides TP;Weiss WA
胶质母细胞瘤是最常见和最具侵袭性的成人脑癌。肿瘤显示雷帕霉素途径的磷脂酰肌醇 3 激酶机制靶点频繁失调。虽然许多小分子靶向 PI3K-AKT-mTOR 轴，但它们的临床前和临床疗效有限。治疗失败的原因包括药物进入大脑的渗透性差，以及观察到阻断 PI3K 或 AKT 对神经胶质瘤下游 mTOR 活性影响最小。使用变构 mTOR 抑制剂（雷帕霉素和 rapalogs）治疗胶质母细胞瘤患者的临床试验也不成功或不确定，部分原因是雷帕霉素不能有效地阻断 mTORC1 靶标 4EBP1，并且还会反馈激活 PI3K-AKT 信号传导。 mTOR 激酶 (TORKi) 抑制剂（例如 TAK-228/MLN0128）与 mTOR 激酶的 ATP 和底物结合袋正位相互作用，在体外有效阻断 4EBP1，目前正在临床试验中进行研究。临床前研究表明，TORKi 的 mTOR 激酶停留时间很短，我们的数据表明，这种较差的药理学转化为胶质母细胞瘤异种移植物中令人失望的疗效。 RapaLink-1 是一种与雷帕霉素连接的 TORKi，代表了一种针对 4EBP1 具有改进药理学的药物。在这篇综述中，我们阐明了 4EBP1 作为 PI3K-AKT-mTOR 抑制剂在胶质母细胞瘤中疗效的生物标志物的重要性。我们还回顾了 RapaLink-1 阻断 p-4EBP1 的机制数据，并讨论了胶质母细胞瘤中 4EBP1 抑制的未来临床策略。
Glioblastoma is the most common and aggressive adult brain cancer. Tumors show frequent dysregulation of the phosphatidylinositol-3 kinase-mechanistic target of rapamycin pathway. While a number of small molecules target the PI3K-AKT-mTOR axis, their preclinical and clinical efficacy has been limited. Reasons for treatment failure include poor penetration of agents into the brain, and observations that blockade of PI3K or AKT minimally affects downstream mTOR activity in glioma. Clinical trials using allosteric mTOR inhibitors (rapamycin and rapalogs) to treat glioblastoma patients have also been unsuccessful or uncertain, in-part because rapamycin inefficiently blocks the mTORC1 target 4EBP1, and also feeds back to activate PI3K-AKT signaling. Inhibitors of the mTOR kinase (TORKi) such as TAK-228/MLN0128 interact orthosterically with the ATP and substrate-binding pocket of mTOR kinase, efficiently block 4EBP1 in-vitro, and are currently being investigated in the clinical trials. Preclinical studies suggest that TORKi have poor residence times of mTOR kinase, and our data suggests that this poor pharmacology translates into disappointing efficacy in glioblastoma xenografts. RapaLink-1, a TORKi linked to rapamycin, represents a drug with improved pharmacology against 4EBP1. In this review, we clarify the importance of 4EBP1 as a biomarker for the efficacy of PI3K-AKT-mTOR inhibitors in glioblastoma. We also review mechanistic data by which RapaLink-1 blocks p-4EBP1, and discuss future clinical strategies for 4EBP1 inhibition in glioblastoma.