Pediatric low-grade gliomas: biology and molecular targeting.

儿科低级别胶质瘤：生物学和分子靶向。

基本信息

批准号：
9269628
负责人：
Adam Cain Resnick
金额：
$ 36.75万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9269628
关键词：
Address Adult Affect Animal Model Astrocytoma Automobile Driving BRAF gene Biochemical Biological Assay Biological Models Biology Brain Neoplasms Cancer Etiology Cell Line Cell Proliferation Cell fusion Cells Child Childhood Childhood Brain Neoplasm Childhood Glioma Chimeric Proteins Clinical Clinical Trials Collaborations Common Neoplasm Complex DNA Sequence Alteration Data Dependency Diffuse Dimerization Disease Drug resistance Event FRAP1 gene Gene Expression Gene Fusion Generations Genetic Genomics Glioma Goals Growth Histologic Homodimerization In Vitro Investigation Lesion Location Malignant - descriptor Malignant Neoplasms Mediating Membrane Mitogen-Activated Protein Kinases Modeling Molecular Molecular Target Morbidity - disease rate Mus Mutation Neuraxis Newly Diagnosed Outcome Pathway interactions Patients Pharmaceutical Preparations Pharmacology Phosphorylation Positioning Attribute Post-Translational Protein Processing Predisposition Process Progression-Free Survivals Publications Publishing Recurrence Regulation Research Resected Resistance Role Sampling Signal Transduction Solid Neoplasm Therapeutic Therapeutic Clinical Trial Time Tumor Subtype Xenograft procedure base childhood cancer mortality combinatorial dimer fusion gene genome sequencing in vivo Model inhibitor/antagonist leukemia melanoma mutant nerve stem cell novel novel therapeutic intervention novel therapeutics protein complex protein protein interaction public health relevance resistance mechanism response targeted agent targeted treatment therapeutic target transcriptome sequencing tumor tumor progression whole genome

项目摘要

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.

描述（由申请人提供）：作为最常见的实体瘤类别，小儿脑肿瘤是儿童与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。低级神经胶质瘤是最常见的小儿脑肿瘤，每年占所有新诊断的肿瘤的三分之一以上。可以完全切除的低级神经膜瘤具有有利的结果。然而，患有中线病变，传播低级星形胶质细胞瘤的儿童或经历了进一步恶性疾病的低级肿瘤患有与肿瘤相关的明显和治疗相关的病态，并具有无前进的生存期。最近，发现MAPK信号的统一基因组改变代表了这类Tumors，为受影响儿童的定向，有针对性的疗法开辟了新的潜在途径。通过基于细胞的，基因组和动物模型系统，该提案介绍了易感性，焦油的分子机制以及对各种亚型的新型疗法的耐药性和相关的机制，以及BRAF播种的小儿小儿小儿低级低年级脑肿瘤的组合疗法。具体而言，该建议扩展了使用药理学抑制剂的初步数据，这些数据定义了在突变体BRAF融合基因表达的情况下定义了抗药性的独特分子机制和相关的MAPK途径。拟议的研究还基于整个基因组测序工作以及对第二代BRAF抑制剂的初步研究，并定义了新的途径和模型系统，用于识别驱动不同BRAF改变BRAF的中枢神经系统恶性肿瘤的协作突变。拟议研究的目的共同为低级神经胶质瘤提供突变特异性的治疗机会，并进一步定义此类肿瘤的基本生物学。