Molecular Pathogenesis of Pediatric High-grade Glioma

该项目的目标是促进对儿童高阶胶质瘤（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试验提供改进的模型系统。儿童HGGs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。虽然成人HGG的分子遗传学已被广泛研究，但由于患者样本有限，对儿科疾病的了解要少得多。研究材料的缺乏对桥脑桥中出现的HGG（称为弥漫性脑干胶质瘤（BSG））尤其具有挑战性，因为它们不能通过手术治疗。对大量儿童HGG的全面高分辨率分子分析从未报道过。重要的是，儿童和成人HGG的特定基因突变频率存在明显差异，这表明针对成人开发的靶向治疗策略可能不是儿童的最佳方法。我们的提案的基础包括在第一个资助期内开发的新的体外和体内HGG模型，以及用于生物学研究的罕见儿科HGG样本的独特的大量收集。我们将完成儿科HGG的全面高分辨率分析，确定HGG的候选癌基因和肿瘤抑制基因，并测试它们对星形细胞肿瘤发生的贡献，并使用新型小鼠模型来解剖肿瘤抑制功能在体内胶质瘤发生中的作用。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.