儿童脑干胶质瘤DIPG的表观遗传靶向治疗新策略及分子机制

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.

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。

儿童脑干胶质瘤DIPG发病率高、预后极差，是目前儿童脑瘤病人死亡的主要原因之一。近80%的DIPG含有组蛋白H3K27M体细胞突变，由其驱动的表观遗传调控异常在DIPG的发病与治疗中均具有重要作用，其中申请人2015年以共同第一作者发表在《Nature Medicine》上的文章报道了HDAC抑制分子药物能够在预临床肿瘤模型汇中有效治疗DIPG，基于该研究成果的人体临床试验也已经在进行之中，因此从表观遗传角度深入挖掘DIPG新的肿瘤致病分子机制与靶向治疗策略是近年来肿瘤表观遗传领域的研究重点和热点方向之一。本项目以DIPG的病人肿瘤组织标本以及多个病人来源的DIPG原代肿瘤模型为研究对象，从三个方向进一步深入系统的研究了DIPG的表观转录致病机制与靶向策略，其中包括（1）系统探究了DIPG对基因转录活性的依赖性并发现其对靶向超级增强子复合物的BET抑制分子和CDK7抑制分子敏感，且与HDAC抑制分子之间存在显著协同抑制作用。在此基础上还进一步通过肿瘤的超级增强子分析鉴定发现了新的致癌分子机制与潜在细胞起源特征；（2）系统探究了miRNA在DIPG中的致癌功能与分子机制，鉴定发现了系列具有重要致癌作用和潜在药物靶标特性的miRNA，为DIPG的靶向治疗鉴定了新靶标；（3）系统分析了DIPG中表观转录调控因子的致癌作用以及现有表观转录靶向小分子的抗肿瘤活性，鉴定发现了一些新的DIPG依赖表观转录调控因子以及表观转录靶向策略，此外，还在进一步筛选了基于已经进入DIPG治疗人体临床试验的HDAC抑制分子药物的组合靶向策略，这些研究将为深入理解DIPG的肿瘤发生机制和开发新的靶向治疗策略提供了重要的理论参考。由于其中新发现的多个表观转录靶向策略均已有相应的小分子药物进入肿瘤治疗的人体临床试验，因此本项目的研究成果将为DIPG的临床治疗提供重要的新思路和新策略。