儿童脑干胶质瘤DIPG是发病率高且预后极差的恶性儿童脑瘤类型。申请人近年的一系列工作证明了表观遗传调控异常在该肿瘤发病和治疗中均具有重要功能。由其报道的能在预临床肿瘤模型中有效治疗DIPG的HDAC抑制分子药物panobinostat已经进入人体临床试验。基于以上成果，申请人课题组近期通过表观遗传药物库筛选鉴定出CDK7抑制分子THZ1不仅单独应用能有效杀伤DIPG原代肿瘤细胞，还在与panobinostat联合应用时具有协同抑制效应。本项目拟在此基础上，利用多个病人来源的DIPG原代肿瘤模型验证以上表观遗传靶向药物单独应用和组合应用的体外和体内抗肿瘤效果，并解析相关分子机制。这些研究不仅将为开发DIPG的表观遗传靶向治疗新策略提供理论基础，还将通过系统剖析作为THZ1关键效应靶标的表观遗传元件超级增强子挖掘新的致病分子机制和潜在药物靶标，对于认识其发病基础和开发临床应用均具有重大意义。

Pediatric brainstem glioma DIPG is a high-incidence and poor-prognosis type of malignant pediatric brain tumor. Through a series of studies published in recent years, the applicant has demonstrated that epigenetic dysregulation not only plays a critical role in DIPG pathogenesis, but also serves as effective drug target. The FDA-approved HDAC inhibitor drug panobinostat, which was shown in one of his studies that could effectively treat DIPG in preclinical tumor models, has already entered early-phase human clinical trial for DIPG patients. Based on these studies, we recently did a combinatory drug screening against DIPG primary cell line using panobinostat in together with another 95 epigenetic drugs. Our results showed the CDK7 inhibitor THZ1 could not only dramatically inhibit the growth of DIPG cells by itself, but also work synergistically with panobinostat in inhibiting DIPG primary cell lines. Next, we propose to thoroughly test the in vitro and in vivo inhibitory effects of THZ1 alone or in combination with panobinostat against multiple patient-derived DIPG primary tumor models. We will also systematically dissect the related epigenetic mechanisms. Our study will provide strong supports for developing novel targeted epigenetic therapeutic strategy against DIPG. Moreover, our comprehensive analyses of the epigenetic signature called super-enhancer, which has been shown to be the key target of THZ1 in other tumor types, will help unveiling novel oncogenic signatures and drug candidates of DIPG. Therefore, our project will contribute significantly to both understanding tumor biology and finding effective therapy for DIPG.