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， WHO分级IV级）是最常见的原发性脑肿瘤，预后较差。神经肿瘤学的一个共同目标是针对肿瘤进展的分子机制开发治疗方法。这种方法的一个潜在的缺点是，在给定患者的GBM中存在巨大的异质性，因此分子靶点可能会根据其采样的微环境而变化。在神经外科切除这些高度浸润性肿瘤后，关键是直接治疗靠近切除边缘的残留浸润性肿瘤的可药物靶点，而不是大部分切除肿瘤的可药物靶点，因为这些靶点可能存在很大差异。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的不同区域有所不同。下游信号网络和药物靶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II期临床试验，这是一种在胶质瘤细胞中积累的荧光化合物，从而增强了可视化和神经外科切除，并允许定义宏观环境，包括1)会阴坏坏性胶质瘤，2)大块胶质瘤和3)胶质瘤边缘。利用这个新颖的神经外科平台，我们提出定义人类GBMs的时空分子变化，包括转录和磷酸化蛋白谱，EGFR/PDGFRA扩增和多重量子点下游网络激活。我们还研究了患者样本中复发性GBM的分子变化，与原发肿瘤边缘的分子变化相比。在GBM异种移植模型中，使用光激活化合物诱导缺氧和坏死，导致血管闭塞，将用于精确监测分子变异的时空演变。我们假设，转录谱、基因组扩增和可药物酪氨酸激酶在空间和时间上存在差异，并且与大肿瘤相比，残留肿瘤边缘会有所不同。