Hedgehog（Hh）信号通路失调广泛参与肿瘤的发生和发展。目前靶向作用该通路上游受体的SMO抑制分子（SMOi）已进入临床试验，但肿瘤对该类药物存在原发性和获得性抗药性。超级增强子（Super-Enhancer）是一类在肿瘤中具有重要作用的新型表观遗传调控元件。最近，本课题申请人在《Nature Medicine》报道超级增强子的核心组分BRD蛋白是Hh通路重要的表观遗传正调控因子。 BRD蛋白的抑制药物（BETi）能有效的治疗Hh通路失调肿瘤和克服其对SMOi的抗药性。本项目拟在这些重要发现的基础上，以Hh通路失调的鼠源髓母细胞瘤为主要研究对象，深入解析Hh通路失调肿瘤中超级增强子的生物学功能以及BETi治疗该类肿瘤的分子作用机制。这些研究将从独特的表观遗传调控角度剖析Hh通路失调肿瘤的分子致病机制，对于认识肿瘤发病基础具有重要理论意义，也将为开发BETi类型的肿瘤药物提供重要基础。

Aberrant activation of Hedgehog (Hh) signaling pathway contributes to initiation and development of many cancers. Currently the major clinical available targeted drug against Hh-activated cancer is inhibitor of the upstream receptor Smoothened (SMOi), however, acquired and a priori resistance to SMOi occurs. Super-Enhancer (SE) is a novel type of epigenetic element that plays critical roles in many cancers. Our recent study published on Nature Medicine journal reports that BET bromodomain proteins (BRDs), which are core components of SE, play important roles in Hh pathway as positive epigenetic regulators. BET bromodomain inhibitor (BETi) can be used to effectively treat Hh-activated cancer and overcome resistance to SMOi. Based on these findings, we propose to utilize Hh-activated mouse medulloblastoma tumor model, to comprehensively study the biological functions of SE in Hh-activated cancer and dissect the molecular mechanism of BETi therapy against Hh-driven cancer. Our study will comprehensively dissect the molecular mechanism of oncogenesis in Hh-activated cancer through an unique angle of epigenetic regulation, which is important for better understanding the tumor biology. It will also provide crucial support for developing BETi targeted therapy against Hh-activated cancer.