Molecular Pathogenesis of Pediatric High-grade Glioma

本项目的目的是进一步了解儿童高格拉德的分子发病机制， 神经胶质瘤（HGG），确定治疗干预的靶点，并产生改进的模型系统， 生物学研究和临床前测试。儿童HGG占所有儿童CMS肿瘤的15-20%， 预后极差，70-90%的患者在诊断后2年内死亡。同时分子 成人HGG的遗传学已被广泛研究，但对儿科疾病的了解要少得多， 这主要是因为患者样本有限。缺乏用于研究的肿瘤材料尤其具有挑战性 对于HGG发生在脑桥，称为弥漫性脑干胶质瘤（BSG），因为它们没有治疗 外科手术对大量儿童HGG进行了全面的高分辨率分子分析， 从未被报道过。重要的是，在特定基因突变的频率上存在明显差异 儿童和成人HGG之间的差异，表明针对成人开发的靶向治疗策略可能 对孩子来说不是最佳的方法。我们的建议的基础包括新的体外和体内 在第一个资助期内开发的HGG模型，以及独特的大量罕见儿科 用于生物学研究的HGG样品。我们将完成一个全面的高分辨率分析儿科 HGG，鉴定HGG的候选癌基因和肿瘤抑制基因，并测试它们对HGG的贡献。 星形胶质细胞肿瘤发生，并使用新的小鼠模型解剖肿瘤抑制功能， 体内胶质瘤形成。我们的研究将与其他人在这个项目中整合，以确定独特的 儿童HGG潜在的癌症途径和导致儿童脑肿瘤的常见途径。

The goals of this project are to advance understanding of the molecular pathogenesis of pediatric high grad glioma (HGG), identify targets for therapeutic intervention and generate improved model systems for biological study and pre-clinical testing. Pediatric HGGs comprise 15-20% of all pediatric CMS tumors, and carry an abysmal prognosis, with 70-90% of patients dying within 2 years of diagnosis. While the molecular genetics of adult HGG has been investigated extensively, much less is known about the pediatric disease, in large part due to limiting patient samples. The lack of tumor material for research is especially challenging for HGG arising in the pons, termed diffuse brainstem gliomas (BSG), because they are not treated surgically. A comprehensive high-resolution molecular analysis of a large collection of pediatric HGG has never been reported. Importantly, there are distinct differences in the frequency of specific gene mutations between pediatric and adult HGG, indicating that targeted therapeutic strategies developed for adults may not be optimal approaches for children. The foundation for our proposal includes novel in vitro and in vivo models for HGG developed during the first funding period, and a unique large collection of rare pediatric HGG samples for biological studies. We will complete a comprehensive high resolution analysis of pediatric HGG, identify candidate oncogenes and tumor suppressor genes for HGG and test their contribution to astrocytic tumorigenesis, and use novel mouse models to dissect tumor suppressor function in gliomagenesis in vivo. Our studies will be integrated with others in this program project to identify unique cancer pathways underlying pediatric HGG and common pathways leading to pediatric brain tumors.