Identification and Preclinical Evaluation of New Brain Tumor Therapies

描述（由申请人提供）：视路胶质瘤（OPG）是一种由肿瘤性NF 1缺陷型星形胶质细胞组成的脑肿瘤，是受神经纤维瘤病1（NF 1）肿瘤易感综合征影响的个体中第二常见的肿瘤。虽然这些肿瘤通常被认为是“良性”脑肿瘤，但它们的持续生长可导致视力丧失和下丘脑功能障碍（青春期早期）。目前，NF 1 OPG的治疗是基于使用已成功用于治疗其他低级别脑肿瘤的化合物，包括卡铂和替莫唑胺。不幸的是，三分之一的儿童发生肿瘤进展，需要额外的治疗。我们最近开发了一种NF 1相关OPG小鼠模型，并对其进行了广泛的表征，在该模型中，低级视神经和视交叉肿瘤在2个月大时发生。为了提供一种有效的方法来鉴定、初步验证和体内临床前评价适合治疗NF 1相关脑肿瘤患者的新型抗癌化合物，我们启动了一项多学科的治疗发现和临床前化疗测试计划。使用这种基于团队的方法，我们已经确定了两种用于NF 1相关脑肿瘤治疗的新型候选药物，雷帕霉素和AMD 3100，它们在体外抑制NF 1-/-星形胶质细胞生长。在本项目中，我们建议采用Nf 1小鼠OPG模型作为抗肿瘤药物评价的临床前平台。首先，我们计划表征NF 1小鼠OPG模型的视觉生理学和放射学特征，作为肿瘤生长的函数，并响应于常规的人NF 1相关脑肿瘤治疗。其次，我们计划评估雷帕霉素和AMD 3100作为NF 1相关脑肿瘤的潜在疗法。凭借专注于NF 1相关OPG治疗的多学科科学家和临床医生团队的独特组合以及NF 1相关OPG的良好表征小鼠模型的可用性，我们具有独特的优势来建立这样的转化研究计划。

DESCRIPTION (provided by applicant): The optic pathway glioma (OPG), a brain tumor composed of neoplastic NF1-deficient astrocytes, is the second most common tumor in individuals affected with the neurofibromatosis 1 (NF1) tumor predisposition syndrome. While these tumors are often regarded as "benign" brain tumors, their continued growth can result in loss of vision and hypothalamic dysfunction (early puberty). Currently, therapy for NF1 OPG is based on the use of compounds that have been successfully employed to treat other low-grade brain tumors, including carboplatin and temozolamide. Unfortunately, tumor progression occurs in one-third of children, necessitating additional therapy. We have recently developed and extensively characterized a mouse model of NF1-associated OPG, in which low-grade optic nerve and chiasm tumors develop by 2 months of age. In an effort to provide an efficient approach for the identification, initial validation, and in vivo preclinical evaluation of new anti-cancer compounds suitable for the treatment of patients with NF1-associated brain tumors, we have initiated a multidisciplinary therapeutic discovery and preclinical chemotherapy testing program. Using this team-based approach, we have identified two novel drug candidates for NF1 -associated brain tumor therapy, rapamycin and AMD3100, which inhibit Nf1-/- astrocyte growth in vitro. In this project, we propose to employ the Nf1 mouse OPG model as a preclinical platform for anti-tumor drug evaluation. First, we plan to characterize the Nf1 mouse OPG model with respect to visual physiology and radiographic features as a function of tumor growth and in response to conventional human NF1 -associated brain tumor therapy. Second, we plan to evaluate rapamycin and AMD3100 as potential therapies for NF1-associated brain tumors. With the unique combination of a multidisciplinary team of scientists and clinicians focused on NF1-associated OPG therapeutics and the availability of a well-characterized mouse model for NF1- associated OPG, we are uniquely positioned to establish such a translational research program.