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: 9063107
• 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/9063107
• 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; Health; Heterogeneity; Human; Hypoxia; Imagery; Immunohistochemistry; Literature; Malignant neoplasm of brain; Mesenchymal; Molecular; Molecular Evolution; Molecular Target; Monitor; Necrosis; 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; genomic profiles; improved outcome; innovation; neuro-oncology; neurosurgery; novel; outcome forecast; programs; protein profiling; relating to nervous system; targeted treatment; 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(申请人提供)：胶质母细胞瘤(GBM；世界卫生组织IV级)是最常见的原发脑肿瘤，预后很差。神经肿瘤学的一个共同目标是开发针对肿瘤进展分子机制的治疗方法。这种方法的一个潜在的批评者是给定患者的GBM中的巨大异质性，因此分子靶标可能会根据采样的微环境而变化。在神经外科手术切除这些高浸润性肿瘤后，关键是直接针对切除边缘附近残留的浸润性肿瘤的可用药靶点进行治疗，而不是对切除的肿瘤进行直接治疗，因为这两种治疗方法可能有很大不同。我们的初步数据和文献表明，转录程序和EGFR/PDGFRA扩增事件在GBM内的不同区域有所不同。下游信令网络和可用药目标可能表现出类似的变化。我们启动了5-氨基乙酰丙酸(5-ALA)的第二阶段临床试验，这是一种聚集在胶质瘤细胞中的荧光化合物，从而增强了可视化和神经外科手术切除，并允许定义宏观环境，包括1)坏死性胶质瘤，2)块状胶质瘤，3)胶质瘤边缘。利用这个新的神经外科平台，我们提出了定义人类基底膜的时空分子变化，包括转录和磷酸化蛋白谱，EGFR/PDGFRA扩增和多重量子点激活下游网络。我们还研究了与原发肿瘤边缘相比，患者样本中复发的基底膜内的分子变化。一个GBM异种移植模型将被用来精确监测分子变异的空间和时间演变。在该模型中，使用导致血管闭塞的光激活化合物来诱导缺氧和坏死。我们假设，转录谱、基因组扩增和可药物酪氨酸激酶在时间和空间上都不同，与实体瘤相比，残留肿瘤的边缘会有所不同。