Preclinical cancer therapy in a mouse model of neurofibromatosis-1 optic glioma
Preclinical cancer therapy in a mouse model of neurofibromatosis-1 optic glioma
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DOI：
10.1158/0008-5472.can-07-5916
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发表时间：
2008-03-01
期刊：
影响因子：
11.2
通讯作者：
Gutmann, David H.
中科院分区：
文献类型：
--
作者：
Hegedus, Balazs;Banerjee, Debasish;Gutmann, David H.
人类癌症的小鼠模型为在临床前试验中评估新疗法提供了独特的机会。为此，我们分析了三个基因工程小鼠（GEM）模型的低级别胶质瘤导致失活的神经纤维瘤病-1（Nf 1）肿瘤抑制基因或组成性激活的KRas在神经胶质细胞。基于肿瘤增殖、位置和转移率，我们选择了这些Nf 1 GEM模型中的一个用于临床前药物评价。在锰增强磁共振成像检测到视神经胶质瘤后，我们将小鼠随机分为治疗组和对照组。我们首先使用目前用于低级别胶质瘤儿童的常规单药化疗（替莫唑胺）验证了Nf 1视神经胶质瘤模型，并表明治疗导致体内肿瘤细胞增殖减少和凋亡增加以及肿瘤体积减小。由于神经纤维蛋白负调节哺乳动物雷帕霉素靶蛋白（mTOR信号传导），我们表明，体内药理学mTOR抑制导致肿瘤细胞增殖以剂量依赖性方式减少，与肿瘤体积减少相关。有趣的是，没有观察到雷帕霉素和替莫唑胺联合治疗的累加效应。最后，为了确定这些疗法对正常大脑的影响，我们发现影响肿瘤细胞增殖或凋亡的治疗对脑生发区内祖细胞的增殖没有显著影响。总的来说，这些发现表明，这种Nf 1视神经胶质瘤模型可能是一个潜在的临床前基准，用于确定在人类临床试验中成功可能性很高的新疗法。
Mouse models of human cancers afford unique opportunities to evaluate novel therapies in preclinical trials. For this purpose, we analyzed three genetically engineered mouse (GEM) models of low-grade glioma resulting from either inactivation of the neurofibromatosis-1 (Nf1) tumor suppressor gene or constitutive activation of KRas in glial cells. Based on tumor proliferation, location, and penetrance, we selected one of these Nf1 GEM models for preclinical drug evaluation. After detection of an optic glioma by manganese-enhanced magnetic resonance imaging, we randomized mice to either treatment or control groups. We first validated the Nf1 optic glioma model using conventional single-agent chemotherapy (temozolomide) currently used for children with low-grade glioma and showed that treatment resulted in decreased proliferation and increased apoptosis of tumor cells in vivo as well as reduced tumor volume. Because neurofibromin negatively regulates mammalian target of rapamycin (mTOR signaling, we showed that pharmacologic mTOR inhibition in vivo led to decreased tumor cell proliferation in a dose-dependent fashion associated with a decrease in tumor volume. Interestingly, no additive effect of combined rapamycin and temozolomide treatment was observed. Lastly, to determine the effect of these therapies on the normal brain, we showed that treatments that affect tumor cell proliferation or apoptosis did not have a significant effect on the proliferation of progenitor cells within brain germinal zones. Collectively, these findings suggest that this Nf1 optic glioma model may be a potential preclinical benchmark for identifying novel therapies that have a high likelihood of success in human clinical trials.