Pediatric low-grade gliomas: biology and molecular targeting.

描述（由申请人提供）：儿童脑肿瘤是最常见的一类实体肿瘤，是儿童癌症相关死亡的主要原因，超过了包括白血病在内的所有其他癌症。低级别胶质瘤是最常见的儿童脑肿瘤，每年占所有新诊断肿瘤的三分之一以上。可以完全切除的低级别胶质瘤有良好的结果。然而，中线病变、弥散性低度星形细胞瘤或低度肿瘤发生进一步恶性转化的儿童患有显著的肿瘤相关和治疗相关的发病率，无进展生存率低。最近，MAPK信号中统一的基因组改变被发现是这类肿瘤的典型特征，为受影响儿童的定向靶向治疗开辟了新的潜在途径。通过细胞、基因组和动物模型系统，本研究旨在探讨braf改变的儿童低级别脑肿瘤不同亚型和组织病理学的易感性、靶向性的分子机制，以及对新疗法的耐药性的相关机制。具体来说，该提案扩展了利用药理学抑制剂的初步数据，这些抑制剂定义了在突变、braf融合基因表达的情况下，独特的耐药分子机制和相关的MAPK途径的矛盾激活。拟议的研究还建立在全基因组测序工作和第二代BRAF抑制剂的初步研究基础上，并为识别驱动不同BRAF改变的中枢神经系统恶性肿瘤的协同突变定义了新的途径和模型系统。总之，拟议研究的目的将为低级别胶质瘤提供突变特异性治疗机会，并进一步定义这类肿瘤的潜在生物学。

DESCRIPTION (provided by applicant): As the most common class of solid tumors, pediatric brain tumors are the leading cause of cancer-related death in children, outpacing all other cancers including leukemias. Low grade gliomas represent the most common pediatric brain tumors and account for more than one third of all newly diagnosed tumors each year. Low grade gliomas that can be completely resected have favorable outcomes. However, children with midline lesions, disseminated low-grade astrocytomas, or low grade tumors that undergo further malignant transfor- mation suffer from significant tumor-related and treatment-related morbidities and have dismal progression-free survival. Recently, unifying genomic alterations in MAPK signaling have been found to typify this class of tu- mors, opening new potential avenues for directed, targeted therapies for affected children. Through cell-based, genomic, and animal model systems, this proposal addresses the molecular mechanisms of susceptibility, tar- geting, and the associated mechanism(s) of resistance to novel therapies in various subtypes and histopathol- ogies of BRAF-altered pediatric low grade brain tumors. Specifically, the proposal expands on preliminary data utilizing pharmacological inhibitors that define unique molecular mechanisms of resistance and an associated MAPK pathway paradoxical activation in the setting of mutant, BRAF-fusion gene expression. The proposed research also builds on whole genome sequencing efforts and an initial investigation of second-generation BRAF inhibitors and defines new avenues and model systems for identifying collaborating mutations that drive distinct BRAF-altered central nervous system malignancies. Together the aims of the proposed research will provide mutations-specific therapeutic opportunities for low grade gliomas and further define the underlying biology of this class of tumors.