Leveraging Genetically-Engineered Mice to Optimize Pediatric Glioma Management

 描述(由申请人提供)：随着我们进入个性化医疗时代，定义疾病风险和结果的因素变得越来越重要。由于这些决定因素在人类流行病学研究中不容易控制，基因工程小鼠(GEM)品系提供了机械上易于处理的平台，以定义疾病异质性的潜在因素，并将它们转化为风险评估工具和治疗方法。儿童低级别脑肿瘤(胶质瘤)在预测临床进展、优化治疗和改善神经预后方面是一种具有挑战性的疾病。在儿童低度恶性胶质瘤最常见的遗传原因--1型神经纤维瘤病(NF1)中，15%-20%的儿童发展为视路胶质瘤(OPGs)，导致30%-60%的患者视力下降。此外，常规化疗只有50%-60%的儿童病情稳定，而且很少有儿童在治疗后视力得到改善。目前，还不能预测患有NF1-OPG的儿童会出现视觉功能障碍(障碍1)，以及什么治疗最有可能导致肿瘤反应和视力恢复(障碍2)。在过去10年中，作为美国国立癌症研究所小鼠人类癌症模型联合会的一部分，我们利用一系列新的NF1基因突变株来证实：(1)胚系NF1基因突变部分决定了NF1蛋白的表达和功能；(2)雌性，而不是雄性，NF1突变小鼠使视力降低；(3)仅携带NF1基因种系突变的非肿瘤免疫系统样细胞(小胶质细胞)对于小鼠视神经胶质瘤的形成和生长是必需的，(4)小鼠视神经胶质瘤含有胶质瘤干细胞(视神经干细胞)，具有独特的和潜在的可靶向靶向的分子和细胞属性。基于这些发现，我们建议对导致NF1的因素--视神经胶质瘤进展、视力丧失和治疗成功--进行系统的、基于团队的剖析。为此，我们组建了一个跨学科的合作团队，以(A)确定女性对OPG诱导的视力下降的易感性的分子病因学(目标1)，(B)评估胚系NF1基因突变对OPG诱导的视力下降的影响(目标2)，以及(C)与潜在的间质导向的胶质瘤治疗相关的小胶质细胞功能(目标3)，以及(D)从NF1视神经胶质瘤宝石中开发一系列不同的GSC，以开发针对最负责维持肿瘤的细胞的新疗法(目标4)。总的来说，考虑到NF1基因检测的广泛临床可获得性，快速细胞重新编程方面的最新进展，以及在NF1-OPG临床评估和治疗评估方面已被证明具有专业知识的两个大型国际财团的存在，这些研究对人类状况具有直接的可译性。

 DESCRIPTION (provided by applicant): As we enter into an era of personalized medicine, it becomes increasingly important to define the factors that confer disease risk and outcome. Since these determinants cannot be easily controlled in human epidemiological studies, genetically-engineered mouse (GEM) strains provide mechanistically-tractable platforms to define the factors underlying disease heterogeneity and translate them to risk assessment tools and treatments. Pediatric low-grade brain tumors (gliomas) represent one such challenging disease with respect to predicting clinical progression, optimizing treatment, and improving neurologic outcome. In the most common inherited cause for pediatric low-grade glioma, neurofibromatosis type 1 (NF1), 15-20% of children develop optic pathway gliomas (OPGs), leading to visual decline in 30-60% of affected individuals. Moreover, conventional chemotherapy results in disease stabilization in only 50-60% of children, and few experience improvement in their visual acuity following treatment. Currently, it is not possible to predict which child with a NF1-OPG will experience visual dysfunction (Barrier 1) and what treatments are most likely to result in tumor response and lead to visual recovery (Barrier 2). Over the past 10 years, as part of the National Cancer Institute Mouse Models of Human Cancers Consortium, we leveraged a collection of novel Nf1 GEM strains with optic glioma to establish that (1) the germline NF1 gene mutation partly determines NF1 protein expression and function, (2) female, but not male, Nf1 mutant mice with optic glioma have reduced visual acuity, (3) non-neoplastic immune system-like cells (microglia) carrying only a germline NF1 gene mutation are required for murine optic glioma formation and growth, and (4) murine optic gliomas contain glioma stem cells (optic GSCs) with unique, and potentially targetable, molecular and cellular properties. Based on these findings, we propose a systematic, team-based dissection of the factors responsible for NF1-optic glioma progression, vision loss, and therapeutic success. For this initiative, we have assembled a cross- disciplinary collaborative team to (a) define the molecular etiology for female susceptibility to OPG-induced visual decline (Aim 1), (b) assess the impact of the germline NF1 gene mutation on OPG-induced visual decline (Aim 2) as well as (c) microglia function relevant to potential stroma-directed glioma treatments (Aim 3), and (d) exploit a series of distinct GSCs from Nf1 optic glioma GEMs for developing new treatments that uniquely target the cells most responsible for maintaining the tumor (Aim 4). Collectively, these studies have immediate translatability to the human condition, given the wide clinical availability of NF1 genetic testing, recent advances in rapid cellular reprograming, and the existence of two large international consortia with proven expertise in NF1-OPG clinical assessment and therapeutic evaluation.