Disrupting NOTCH Slows Diffuse Intrinsic Pontine Glioma Growth, Enhances Radiation Sensitivity, and Shows Combinatorial Efficacy With Bromodomain Inhibition.
Disrupting NOTCH Slows Diffuse Intrinsic Pontine Glioma Growth, Enhances Radiation Sensitivity, and Shows Combinatorial Efficacy With Bromodomain Inhibition.
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DOI：
10.1097/nen.0000000000000216
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发表时间：
2015-08
影响因子：
3.2
通讯作者：
Raabe EH
中科院分区：
文献类型：
--
作者：
Taylor IC;Hütt-Cabezas M;Brandt WD;Kambhampati M;Nazarian J;Chang HT;Warren KE;Eberhart CG;Raabe EH
NOTCH调节正常发育过程中的干细胞和癌症中的干细胞样细胞，但NOTCH在致死性小儿脑肿瘤弥漫性内在脑桥胶质瘤（DIPG）中的作用仍然未知。由于DIPG表达干细胞因子，如SOX 2和MYCN，我们假设NOTCH活性对DIPG生长至关重要。我们确定原代DIPG表达高水平的NOTCH受体、配体和下游效应物。用γ-分泌酶抑制剂MRK 003处理DIPG细胞系JHH-DIPG 1和SF 7761可抑制NOTCH效应物HES 1、HES 4、HES 5的水平，抑制DIPG生长75%，并导致3倍的凋亡诱导。靶向经典NOTCH途径的短发夹RNA引起类似的效果。用MRK 003预处理DIPG细胞抑制了90%以上的克隆生长，并增强了放射治疗的疗效。DIPG中MYCN的高水平使我们测试了用布罗莫结构域抑制剂JQ 1和MRK 003的序贯疗法，并且我们发现JQ 1和MRK 003抑制DIPG生长并诱导凋亡。总之，这些结果表明，DIPG中NOTCH和MYCN的双重靶向可能是DIPG中的有效治疗策略，并且在放射治疗期间添加γ-分泌酶抑制剂可能在初始或再照射期间有效。
NOTCH regulates stem cells during normal development and stem-like cells in cancer but the roles of NOTCH in the lethal pediatric brain tumor diffuse intrinsic pontine glioma (DIPG) remain unknown. Because DIPGs express stem cell factors such as SOX2 and MYCN, we hypothesized that NOTCH activity would be critical for DIPG growth. We determined that primary DIPGs expressed high levels of NOTCH receptors, ligands, and downstream effectors. Treatment of the DIPG cell lines JHH-DIPG1 and SF7761 with the γ-secretase inhibitor MRK003 suppressed the level of the NOTCH effectors HES1, HES4, HES5, inhibited DIPG growth by 75%, and caused a 3-fold induction of apoptosis. Short hairpin RNAs targeting the canonical NOTCH pathway caused similar effects. Pre-treatment of DIPG cells with MRK003 suppressed clonogenic growth by more than 90% and enhanced the efficacy of radiation therapy. The high level of MYCN in DIPG led us to test sequential therapy with the bromodomain inhibitor JQ1 and MRK003, and we found that JQ1 and MRK003 inhibited DIPG growth and induced apoptosis. Together, these results suggest that dual targeting of NOTCH and MYCN in DIPG may be an effective therapeutic strategy in DIPG and that adding a γ-secretase inhibitor during radiation therapy may be efficacious initially or during re-irradiation.