靶向Gli3 processing调控Shh信号通路的新型抑制剂治疗儿童髓母细胞瘤及相关作用机制研究

Gli3负反馈调节作用维持了Shh信号通路处于适当的活化水平，保障了组织器官的正常发育。Gli3负反馈调节障碍是儿童髓母细胞瘤（MB）发生的前提。目前Shh通路抑制剂的研发主要靶向膜蛋白Smo，然而已上市的两个Smo拮抗剂却因严重的“on-target”毒性且易引发耐药不能用于MB的治疗。本项目已证明，通过促进Gli3 processing可以恢复Gli3对于Shh通路的负反馈调节，使其从异常激活水平降至正常生理水平。此外，Gli3位于Smo的下游，能够克服Smo拮抗剂所引发的耐药。本项目建立了以Gli3 processing为靶点的HTS模型，并从已上市药物库中筛选出活性化合物Vorinostat(Vor)，体外研究表明Vor显著抑制原代MB细胞的增殖及其Shh通路。本项目拟对Vor进行深入系统的药理学和药效学研究。本课题的开展将为MB及其它Shh通路相关肿瘤提供新的治疗靶点和治疗策略。

The negative feedback loop mediated by Gli3 maintained the Shh signaling pathway at a physiologic level of activation, providing a guarantee for the normal development of tissues and organs. Disruption of Gli3 negative feedback can result in aberrant activation of the Shh pathway that eventually leads to the tumorigenesis of medulloblastoma. The current research on Shh signaling pathway inhibitors mainly targets the membrane protein smoothened (Smo). However, the two Smo antagonists approved by FDA have severe “on-target” toxicity and are prone to drug resistance, and can not be used for the treatment of medulloblastoma. Our recent study shows that Gli3 negative feedback loop can be restored by promoting Gli3 processing, which can reduce Shh signaling pathway from abnormal activation to normal physiological level. In addition, Gli3 is located downstream of Smo and can overcome resistance induced by Smo antagonists. High throughput drug screening (HTS) models targeting Gli3 processing have been established in our study, and Vorinostat was screened out from FDA-approved drug library. In vitro studies have shown that Vorinostat inhibits the proliferation of primary MB cells and Shh signaling pathway effectively. This project aims to elucidate the anti-MB effects and mechanisms of Vorinostat intensively. This study will provide a novel and potent target and a new therapeutic strategy for medulloblastoma and other Shh signaling pathway related tumors.