Pediatric low-grade gliomas: biology and molecular targeting.

儿科低级别胶质瘤：生物学和分子靶向。

• 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
• 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

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型，儿科脑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科脑肿瘤，占每年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具有良好的结局。然而，患有中线病变、播散性低级别星形细胞瘤或经历进一步恶性转化的低级别肿瘤的儿童患有显著的肿瘤相关和治疗相关的发病率，并且无进展生存率低。最近，已经发现MAPK信号传导中的统一基因组改变是这类肿瘤的典型，为受影响儿童的定向靶向治疗开辟了新的潜在途径。通过基于细胞的、基因组的和动物模型系统，该提案阐述了BRAF改变的儿科低级别脑肿瘤的各种亚型和组织病理学中易感性、靶向的分子机制以及对新疗法耐药的相关机制。具体而言，该提案扩展了利用药理学抑制剂的初步数据，这些药理学抑制剂定义了在突变体BRAF融合基因表达的背景下的抗性和相关MAPK通路矛盾激活的独特分子机制。拟议的研究还建立在全基因组测序工作和第二代BRAF抑制剂的初步研究的基础上，并定义了新的途径和模型系统，用于识别驱动不同BRAF改变的中枢神经系统恶性肿瘤的协作突变。这项研究的目的将为低级别胶质瘤提供突变特异性治疗机会，并进一步确定这类肿瘤的潜在生物学。