Hegedus Balazs, Banerjee Debasish, Yeh Tu-Hsueh, Rothermich Stefan, Perry Arie, Rubin Joshua B, Garbow Joel R, Gutmann David H
Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Cancer Res. 2008 Mar 1;68(5):1520-8. doi: 10.1158/0008-5472.CAN-07-5916.
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.
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，我们分析了三种低级别胶质瘤的基因工程小鼠（GEM）模型，这些模型是由神经纤维瘤病1型（Nf1）肿瘤抑制基因失活或胶质细胞中KRas的组成性激活导致的。基于肿瘤增殖、位置和发生率，我们选择了其中一种Nf1 GEM模型进行临床前药物评估。通过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或对照组。我们首先使用目前用于低级别胶质瘤儿童的传统单药化疗（替莫唑胺）验证了Nf1视神经胶质瘤模型，结果表明治疗导致体内肿瘤细胞增殖减少、凋亡增加以及肿瘤体积减小。由于神经纤维瘤蛋白负向调节哺乳动物雷帕霉素靶蛋白（mTOR）信号通路，我们表明体内药理学抑制mTOR会导致肿瘤细胞增殖以剂量依赖的方式减少，同时肿瘤体积减小。有趣的是，未观察到雷帕霉素和替莫唑胺联合治疗的相加效应。最后，为了确定这些疗法对正常大脑的影响，我们表明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Nf1视神经胶质瘤模型可能是一种潜在的临床前基准，用于识别在人类临床试验中具有高成功可能性的新疗法。
