Molecular Pathogenesis of Pediatric High-grade Glioma

本项目的目标是促进对儿童高分化症分子发病机制的了解。 胶质瘤(HGG)，确定治疗干预的目标并生成改进的模型系统 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%，以及 预后极差，70%-90%的患者在确诊后两年内死亡。而分子 成人HGG的遗传学已经被广泛研究，但对这种儿科疾病的了解要少得多 很大程度上是由于患者样本的限制。缺乏用于研究的肿瘤材料尤其具有挑战性。 对于发生在脑桥的HGG，称为弥漫性脑干胶质瘤(BSG)，因为它们没有得到治疗 从外科手术开始。对一大批儿童HGG进行全面的高分辨率分子分析 从未被报道过。重要的是，特定基因突变的频率有明显的差异。 儿童和成人HGG之间的差异，表明为成人开发的靶向治疗策略可能 并不是儿童的最佳方法。我们建议的基础包括体外创新和体内创新。 在第一个资助期内开发了HGG模型，以及独特的大量稀有儿科 用于生物学研究的HGG样本。我们将完成对儿科疾病的全面高分辨率分析 HGG，确定HGG的候选癌基因和抑癌基因，并测试它们对 星形细胞肿瘤的发生，并使用新的小鼠模型来剖析肿瘤抑制功能 体内的胶质瘤形成。我们的研究将与该计划项目中的其他人相结合，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.