Molecular therapy targeting Sonic hedgehog and hepatocyte growth factor signaling in a mouse model of medulloblastoma.
Molecular therapy targeting Sonic hedgehog and hepatocyte growth factor signaling in a mouse model of medulloblastoma.
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DOI：
10.1158/1535-7163.mct-10-0486
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发表时间：
2010-09
影响因子：
5.7
通讯作者：
Fults DW
中科院分区：
文献类型：
--
作者：
Coon V;Laukert T;Pedone CA;Laterra J;Kim KJ;Fults DW
基因工程小鼠的使用为儿童脑肿瘤髓母细胞瘤的分子发病机制提供了见解，并揭示了有希望的治疗靶点。小鼠小脑神经祖细胞中异位表达Sonic Hedgehog （Shh）可诱导成神经管细胞瘤，而肝细胞生长因子（HGF）的共表达可增强Shh诱导的肿瘤形成。为了确定Shh+HGF驱动的髓母细胞瘤是否对Shh信号阻断有反应，以及针对HGF和Shh信号通路的联合治疗是否可以增强治疗反应，我们在小鼠中进行了一项生存研究。我们通过逆转录病毒介导的Shh和HGF的表达诱导成神经管细胞瘤，之后我们用(a) HGF中和单克隆抗体L2G7， (b) Shh信号抑制剂环巴胺，(c) sh中和单克隆抗体5E1， (d) L2G7+环巴胺，或(e) L2G7+5E1对小鼠进行全身处理。我们报道，针对HGF信号或Shh信号的单药治疗延长了生存期，抗HGF治疗比sh靶向治疗具有更持久的反应。L2G7+5E1联合治疗对累积生存期的影响与L2G7单药治疗相当，但L2G7+环巴胺治疗的累积生存期更差。Shh和hgf靶向治疗抑制肿瘤生长的主要机制是肿瘤细胞中有效的凋亡死亡反应，辅以对增殖的较弱抑制作用。我们观察到，与单药治疗相比，联合治疗不能改善甚至降低携带Shh+HGF诱导的髓母细胞瘤小鼠的存活率，这强调了在已知靶向通路活跃的肿瘤动物模型中进行分子靶向治疗临床前测试的重要性。
The use of genetically engineered mice has provided insights into the molecular pathogenesis of the pediatric brain tumor medulloblastoma and revealed promising therapeutic targets. Ectopic expression of Sonic Hedgehog (Shh) in cerebellar neural progenitor cells induces medulloblastomas in mice, and coexpression of hepatocyte growth factor (HGF) enhances Shh-induced tumor formation. To determine whether Shh+HGF–driven medulloblastomas were responsive to Shh signaling blockade and whether treatment response could be enhanced by combination therapy targeting both HGF and Shh signaling pathways, we carried out a survival study in mice. We induced medulloblastomas by retrovirus-mediated expression of Shh and HGF, after which we treated the mice systemically with (a) HGF-neutralizing monoclonal antibody L2G7, (b) Shh signaling inhibitor cyclopamine, (c) Shh-neutralizing monoclonal antibody 5E1, (d) L2G7+cyclopamine, or (e) L2G7+5E1. We report that monotherapy targeting either HGF signaling or Shh signaling prolonged survival and that anti-HGF therapy had a more durable response than Shh-targeted therapy. The effect of L2G7+5E1 combination therapy on cumulative survival was equivalent to that of L2G7 monotherapy and that of L2G7+cyclopamine therapy was worse. The principal mechanism by which Shh- and HGF-targeted therapies inhibited tumor growth was a potent apoptotic death response in tumor cells, supplemented by a weaker suppressive effect on proliferation. Our observation that combination therapy either failed to improve or even reduced survival in mice bearing Shh+HGF induced medulloblastomas compared with monotherapy underscores the importance of preclinical testing of molecular-targeted therapies in animal models of tumors in which the targeted pathways are known to be active.