Suppression of the Shh pathway using a small molecule inhibitor eliminates medulloblastoma in Ptc1+/- p53-/- mice
Suppression of the Shh pathway using a small molecule inhibitor eliminates medulloblastoma in Ptc1+/- p53-/- mice
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DOI：
10.1016/j.ccr.2004.08.019
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发表时间：
2004-09-01
期刊：
影响因子：
50.3
通讯作者：
Curran, T
中科院分区：
文献类型：
--
作者：
Romer, JT;Kimura, H;Curran, T
髓母细胞瘤是儿童最常见的恶性脑肿瘤。目前的治疗与主要的长期副作用有关；因此，需要开发针对这种癌症的特定分子缺陷的新的无毒治疗方法。我们使用髓母细胞瘤的小鼠模型来证明抑制Sonic Hedgehog(Shh)通路为髓母细胞瘤提供了一种新的治疗方法。Shh途径的小分子抑制剂HhAntag阻断了Smoothens在髓母细胞瘤小鼠中的功能。这导致了几个在髓母细胞瘤中高表达的基因被抑制，抑制了细胞增殖，增加了细胞死亡，并在最高剂量下完全根除了肿瘤。HhAntag的长期治疗延长了髓母细胞瘤的无生存期。这些发现支持Shh拮抗剂治疗髓母细胞瘤的发展。
Medulloblastoma is the most common malignant pediatric brain tumor. Current treatment is associated with major long-term side effects; therefore, new nontoxic therapies, targeting specific molecular defects in this cancer, need to be developed. We use a mouse model of medulloblastoma to show that inhibition of the Sonic Hedgehog (Shh) pathway provides a novel therapy for medulloblastoma. A small molecule inhibitor of the Shh pathway, HhAntag, blocked the function of Smoothened in mice with medulloblastoma. This resulted in suppression of several genes highly expressed in medulloblastoma, inhibition of cell proliferation, increase in cell death and, at the highest dose, complete eradication of tumors. Long-term treatment with HhAntag prolonged medulloblastoma-free survival. These findings support the development of Shh antagonists for the treatment of medulloblastoma.