Molecular Target Variation Across Environments and at Margins of Glioblastoma

不同环境和胶质母细胞瘤边缘的分子靶标变化

• 批准号: 8502036
• 负责人: DANIEL J BRAT
• 金额: $ 45.52万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-06 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8502036
• 关键词: Aminolevulinic Acid; CCAAT-Enhancer-Binding Proteins; Cells; Clinical; Data; Development; EGFR gene; Environment; Epidermal Growth Factor Receptor; Event; Evolution; Excision; Gene Amplification; Genes; Genomics; Glioblastoma; Glioma; Goals; Heterogeneity; Human; Hypoxia; Imagery; Immunohistochemistry; Literature; Malignant neoplasm of brain; Mesenchymal; Molecular; Molecular Evolution; Molecular Target; Monitor; Necrosis; Outcome; PDGFRA gene; Patients; Phase; Phase II Clinical Trials; Primary Brain Neoplasms; Primary Neoplasm; Property; Protein Tyrosine Kinase; Proteins; Quantum Dots; Recurrence; Resected; Residual Tumors; Residual state; STAT3 gene; Sampling; Signal Transduction; Subgroup; Testing; The Cancer Genome Atlas; Thrombosis; Time; Tumor Biology; Variant; Xenograft Model; c-erbB-1 Proto-Oncogenes; improved; innovation; neuro-oncology; neurosurgery; novel; outcome forecast; programs; protein profiling; public health relevance; relating to nervous system; therapeutic target; therapy development; tumor; tumor progression

DESCRIPTION (provided by applicant): Glioblastoma (GBM; WHO grade IV) is the most frequent primary brain tumor and has a dismal prognosis. A common goal in neuro-oncology is to develop therapies targeted at molecular mechanisms of tumor progression. One potential detractor to such approaches is the tremendous heterogeneity within a given patient's GBM, such that molecular targets could vary depending on the micro-environment from which they are sampled. Following neurosurgical resection of these highly infiltrative tumors, it will be criticalto direct therapies at druggable targets present at the residual invasive tumor near the resection margin, rather than at those of the bulk resected tumor, since these could differ substantially. Our preliminary data and the literature suggest that transcriptional programs and EGFR/PDGFRA amplification events vary across regions within GBM. Downstream signaling networks and druggable targets likely show similar variation. We initiated a Phase II clinical tria of 5-Aminolevulinic Acid (5-ALA), a fluorescent compound that accumulates in glioma cells, thereby enhancing visualization and neurosurgical resection and allowing definition of macro-environments that include 1) perinecrotic glioma, 2) bulk glioma, and 3) glioma margin. Using this novel neurosurgical platform, we propose to define spatial and temporal molecular variations of human GBMs including transcriptional and phospho-protein profiles, EGFR/PDGFRA amplification and downstream network activation by multiplex quantum dots. We also investigate molecular alterations that evolve within recurrent GBM in patient samples as compared to those present at the tumor margin of the primary tumor. A GBM xenograft model in which hypoxia and necrosis are induced using photo-activated compounds that cause vaso-occlusion will be used to precisely monitor spatial and temporal evolution of molecular variation. We hypothesize that the transcriptional profiles, genomic amplification, and druggable tyrosine kinases vary spatially and temporally, and will differ at the residual tumor margin as compared to the bulk tumor.

描述（由申请人提供）：胶质母细胞瘤（GBM; WHO IV级）是最常见的原发性脑肿瘤，并且预后较为沮丧。神经肿瘤学的一个共同目标是开发针对肿瘤进展的分子机制的疗法。这种方法的一种潜在不利因素是在给定患者的GBM内的巨大异质性，因此分子靶标可能会根据对它们采样的微环境而变化。在对这些高度浸润性肿瘤进行神经外科切除术后，在切除缘附近残留的浸润性肿瘤的可药物靶标的直接疗法将是至关重要的，而不是在大块切除肿瘤的肿瘤上，因为这些肿瘤可能会有很大差异。我们的初步数据和文献表明，转录程序和EGFR/PDGFRA放大事件在GBM内的地区各个区域各不相同。下游信号网络和可毒目标可能显示出相似的变化。我们启动了5-氨基甲基甲酸（5-ALA）的II期临床三细胞，这是一种荧光化合物，可在神经胶质瘤细胞中积聚，从而增强可视化和神经外科外科切除术，并允许对宏观环境的定义，以包括1）包含1）perinecrototic Glioma，2）Bulk Glioma和3）Bulk Glioma和3）。使用这个新型的神经外科平台，我们建议定义人类GBM的空间和时间分子变化，包括转录和磷酸 - 蛋白质谱，EGFR/PDGFRA扩增和通过多重量子点激活下游网络激活。我们还研究了与原发性肿瘤肿瘤边缘相比，患者样品中复发性GBM内演变的分子改变。一种GBM异种移植模型，其中使用引起血管封闭的光激活化合物诱导低氧和坏死模型，可用于精确监测分子变异的空间和时间演化。我们假设转录曲线，基因组扩增和可药物检测的酪氨酸激酶在空间和时间上变化，并且与散装肿瘤相比，残留肿瘤边缘会有所不同。