Molecular Pathogenesis of Pediatric High-grade Glioma

该项目的目标是促进对儿童高级别胶质瘤(HGG)分子发病机制的了解，确定治疗干预的靶点，并为生物学研究和临床前测试产生改进的模型系统。儿童HGG占所有儿童CMS肿瘤的15%-20%，预后极差，70%-90%的患者在确诊后2年内死亡。虽然成人HGG的分子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。缺乏可供研究的肿瘤材料对发生在脑桥的HGG尤其具有挑战性，这种肿瘤被称为弥漫性脑干胶质瘤(BSG)，因为它们不需要手术治疗。对一大批儿童HGG进行全面的高分辨率分子分析尚未见报道。重要的是，在儿童和成人HGG中，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。我们建议的基础包括在第一个资助期开发的新的HGG体外和体内模型，以及用于生物学研究的独特的大量稀有儿科HGG样本。我们将完成对儿童HGG的全面高分辨率分析，寻找HGG的候选癌基因和抑癌基因，并检测它们在星形细胞肿瘤发生中的作用，并使用新的小鼠模型在体内剖析肿瘤抑制基因在胶质瘤形成中的作用。我们的研究将与该计划项目中的其他研究相结合，以确定儿童HGG潜在的独特癌症途径和导致儿童脑瘤的常见途径。

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.