Targeting Wee1 for the treatment of pediatric high-grade gliomas
Targeting Wee1 for the treatment of pediatric high-grade gliomas
复制标题
DOI：
10.1093/neuonc/not220
复制
发表时间：
2014-03-01
期刊：
影响因子：
15.9
通讯作者：
Haas-Kogan, Daphne A.
中科院分区：
文献类型：
--
作者：
Mueller, Sabine;Hashizume, Rintaro;Haas-Kogan, Daphne A.
背景我们研究了Wee 1抑制剂MK-1775联合放射治疗儿童高级别胶质瘤（HGG），包括弥漫性桥脑胶质瘤（DIPG）的疗效。使用Agilent 4x 44 Karray对38个原发性小儿神经胶质瘤（3个I级、10个II级、11个III级、14个IV级）和8个正常脑样品进行基因表达分析。在儿童和成人HGG细胞系（n 6）中进行了克隆形成存活试验，以评估MK-1775的放射增敏作用。通过测量γ-H2 AX（双链DNA断裂的标志物）的蛋白质水平来评价DNA修复能力。在2种不同的儿科HGG原位移植模型中评估了MK-1775与辐射的体内活性，其中1种模型来自携带BRAF（V600 E）突变的基因工程小鼠，1种模型来自肿瘤细胞来源于患者的DIPG的异种移植模型。结果。Wee 1在儿童HGG中过度表达，表达增加与恶性程度呈正相关（III + IV级与I + II级的P = 0.007），在DIPG中表达显著高。MK-1775和放射联合治疗降低了克隆形成存活率，并增加了γ-H2 AX的表达，其程度大于单独放射治疗。最后，MK-1775和放射联合给药与单纯放射给药相比，对移植原位HGG和DIPG肿瘤小鼠的生存获益更大（BRAF（V600 E）模型P = .0061和DIPG脑干模型P = .0163）。我们的研究结果突出了MK-1775作为一种有前途的新治疗剂，可与放射联合用于治疗儿科HGG，包括DIPG。
Background. We investigated the efficacy of the Wee1 inhibitor MK-1775 in combination with radiation for the treatment of pediatric high-grade gliomas (HGGs), including diffuse intrinsic pontine gliomas (DIPGs).Methods. Gene expression analysis was performed for 38 primary pediatric gliomas (3 grade I, 10 grade II, 11 grade III, 14 grade IV) and 8 normal brain samples using the Agilent 4 x 44 Karray. Clonogenic survival assays were carried out in pediatric and adult HGG cell lines (n 6) to assess radiosensitizing effects of MK-1775. DNA repair capacity was evaluated by measuring protein levels of gamma-H2AX, a marker of double strand DNA breaks. In vivo activity of MK-1775 with radiation was assessed in 2 distinct orthotopic engraftment models of pediatric HGG, including 1 derived from a genetically engineered mouse carrying a BRAF(V600E) mutation, and 1 xenograft model in which tumor cells were derived from a patient's DIPG.Results. Wee1 is over expressed in pediatric HGGs, with increasing expression positively correlated with malignancy (P = .007 for grade III + IV vs I + II) and markedly high expression in DIPG. Combination treatment of MK-1775 and radiation reduced clonogenic survival and increased expression of gamma-H2AX to a greater extent than achieved by radiation alone. Finally, combined MK-1775 and radiation conferred greater survival benefit to mice bearing engrafted, orthotopic HGG and DIPG tumors, compared with treatment with radiation alone (BRAF(V600E) model P = .0061 and DIPG brainstem model P = .0163).Conclusion. Our results highlight MK-1775 as a promising new therapeutic agent for use in combination with radiation for the treatment of pediatric HGGs, including DIPG.