Preclinical evaluation of radiation and perifosine in a genetically and histologically accurate model of brainstem glioma.
Preclinical evaluation of radiation and perifosine in a genetically and histologically accurate model of brainstem glioma.
复制标题
在遗传学和组织学精确的脑干神经胶质瘤模型中，辐射和perifosine的临床前评估。
DOI：
10.1158/0008-5472.can-09-2503
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发表时间：
2010-03-15
期刊：
影响因子：
11.2
通讯作者：
Holland EC
中科院分区：
文献类型：
--
作者：
Becher OJ;Hambardzumyan D;Walker TR;Helmy K;Nazarian J;Albrecht S;Hiner RL;Gall S;Huse JT;Jabado N;MacDonald TJ;Holland EC
脑干胶质瘤(BSG)是一种罕见的中枢神经系统肿瘤，多发生在儿童，通常预示着预后特别差。我们报告了使用RCAS/TV-a系统开发的BSG基因工程小鼠模型及其在临床前试验中的实施。应用免疫组织化学方法，我们发现67%的儿童BSG中高表达PDGFRα。基于这一观察，我们通过在新生Nestin TV-a小鼠的后颅窝过度表达PDGF-B来诱导低度BSG。为了产生高级别的BSG，我们过度表达PDGF-B并结合Ink4a-ARF缺失，因为这个基因位点在高级别的儿科BSG中通常丢失。我们表明，这些小鼠BSG的可能起源细胞存在于第四脑室和大脑导水管的底部。对这些高级别BSG的照射显示，当2、6和10Gy单剂量照射时，TUNEL阳性核的百分率显著增加，仅6Gy和10Gy时显著诱导细胞周期停滞。AKT信号转导阻断剂Perifosine在6、24、72h显著诱导高级别BSG模型中TUNEL阳性核，但与10Gy联用时，其阳性核百分率与单独10Gy组相比无明显增加。生存分析表明，单次照射10Gy后，小鼠的生存时间显著延长了27%(p=0.0002)，而周磷脂的作用不明显(p=0.92)。与单独使用10Gy组相比，Perifosine+10Gy组的存活率没有显著提高(p=0.23)。这种PDGF诱导的BSG模型可以作为测试新药物的临床前工具。
Brainstem gliomas (BSGs) are a rare group of CNS tumors that arise mostly in children and usually portend a particularly poor prognosis. We report the development of a genetically engineered mouse model of BSG using the RCAS/tv-a system and its implementation in preclinical trials. Using immunohistochemistry we found that PDGFRα is overexpressed in 67% of pediatric BSGs. Based on this observation, we induced low-grade BSGs by overexpressing PDGF-B in the posterior fossa of neonatal Nestin tv-a mice. To generate high-grade BSGs, we overexpressed PDGF-B in combination with Ink4a-ARF loss, given that this locus is commonly lost in high-grade pediatric BSGs. We show that the likely cells-of-origin for these mouse BSGs exist on the floor of the 4th ventricle and cerebral aqueduct. Irradiation of these high-grade BSGs shows that while 2, 6, and 10 Gy single doses significantly increased the percent of TUNEL-positive nuclei, only 6, and 10 Gy significantly induces cell-cycle arrest. Perifosine, an inhibitor of AKT signaling significantly induced TUNEL-positive nuclei in this high-grade BSG model, but in combination with 10 Gy, it did not significantly increase the percent of TUNEL-positive nuclei relative to 10 Gy alone at 6, 24, and 72 hours. Survival analysis demonstrated that a single dose of 10 Gy significantly prolonged survival by 27% (p=0.0002) but perifosine did not (p=0.92). Perifosine + 10Gy did not result in a significantly increased survival relative to 10Gy alone (p=0.23). This PDGF-induced BSG model can serve as a preclinical tool for the testing of novel agents.