期刊
CANCER LETTERS
卷 400, 期 -, 页码 110-116出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2017.04.019
关键词
Pediatric brain tumor; Sapanisertib; mTOR; INK128; MLN0128
类别
资金
- Cure Starts Now Foundation
- Giant Food Foundation
- NCI [P30 CA006973]
- National Institute of Health/National Cancer Institute [T32CA60441]
- Smashing Walnuts/Piedmont community
- Goldwin Foundation
Diffuse intrinsic pontine glioma (DIPG) is an invasive and treatment-refractory pediatric brain tumor. Primary DIPG tumors harbor a number of mutations including alterations in PTEN, AKT, and PI3K and exhibit activation of mammalian Target of Rapamycin Complex 1 and 2 (mTORC1/2). mTORC1/2 regulate protein translation, cell growth, survival, invasion, and metabolism. Pharmacological inhibition of mTORC1 is minimally effective in DIPG. However, the activity of dual TORC kinase inhibitors has not been examined in this tumor type. Nanomolar levels of the mTORC1/2 inhibitor TAK228 reduced expression of p-AKT(S473) and p-S6(S240/244) and suppressed the growth of DIPG lines JHH-DIPG1, SF7761, and SU-DIPG-XIII. TAK228 induced apoptosis in DIPG cells and cooperated with radiation to further block proliferation and enhance apoptosis. TAK228 monotherapy inhibited the tumorigenicity of a murine orthotopic model of DIPG, more than doubling median survival (p = 0.0017) versus vehicle. We conclude that dual mTOR inhibition is a promising potential candidate for DIPG treatment. (C) 2017 Elsevier B.V. All rights reserved.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据