Molecular Pathogenesis of Pediatric High-grade Glioma

该项目的目标是促进对儿童高格拉德胶质瘤（HGG）分子发病机制的理解，确定治疗干预的靶点，并为生物学研究和临床前测试生成改进的模型系统。小儿HGG占所有小儿CMS肿瘤的15-20%，预后极差，70-90%的患者在诊断后2年内死亡。虽然成人HGG的分子遗传学已被广泛研究，但对儿科疾病知之甚少，这在很大程度上是由于患者样本有限。缺乏肿瘤材料的研究是特别具有挑战性的HGG发生在脑桥，称为弥漫性脑干胶质瘤（BSG），因为他们没有手术治疗。一个全面的高分辨率的分子分析的一个大集合的儿科HGG从未被报道。重要的是，儿童和成人HGG之间特定基因突变的频率存在明显差异，这表明为成人开发的靶向治疗策略可能不是儿童的最佳方法。我们提案的基础包括在第一个资助期内开发的HGG的新型体外和体内模型，以及用于生物学研究的罕见儿科HGG样本的独特大量收集。我们将完成一个全面的高分辨率分析儿科HGG，确定候选癌基因和肿瘤抑制基因HGG和测试他们的贡献星形胶质细胞肿瘤，并使用新的小鼠模型来解剖肿瘤抑制功能在体内胶质瘤。我们的研究将与该项目中的其他研究相结合，以确定儿童HGG的独特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.