Xenograft Model for Studying Amplified EGFR in GBM

用于研究 GBM 中扩增的 EGFR 的异种移植模型

• 批准号: 6825627
• 负责人: Charles David James
• 金额: $ 30.12万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6825627
• 关键词: apoptosis; astrocytoma; athymic mouse; biological models; cell proliferation; clinical research; epidermal growth factor; fluorescent in situ hybridization; growth factor receptors; human tissue; magnetic resonance imaging; model design /development; neoplastic growth; phospholipase C; phosphorylation; receptor expression; small molecule; terminal nick end labeling; xenotransplantation

DESCRIPTION: (provided by applicant) Amplification of EGFR was the first gene alteration identified in the most common and most malignant of primary brain tumors, glioblastoma (GBM). In spite of nearly 2 decades of GBM-EFGR research, and the substantial body of information that has accumulated from the related investigations, little effort has been directed to the development of an in vivo system for facilitating studies of the molecular biology and therapeutic targeting of highly-expressed Egf receptor in GBMs with amplified EGFR. This proposal is for the purpose of addressing this deficiency, and for using the model(s) derived from this work for addressing fundamental issues involving EGFR amplification in GBM. The model we are developing and characterizing, serially-transplantable GBM xenograft lines that maintain EGFR amplification, will be used to accomplish the following specific aims: Specific Aim 1: Identify changes in the molecular and tumor biological properties associated with the establishment of cell lines from GBM xenograft with EFGR amplification. Specific Aim 2 : Confirm the preliminary observations of an in vivo relationship between EGFR amplification and elevated PLCy phosphorylation, and identify molecular and tumor biologic consequences of this relationship. Specific Aim 3 : Determine and intrepret, with respect to EFGR amplification status, the in vivo effects of small molecule inhibitors of Egf receptor on the orthotopic growth, invasion, vasularization, and apoptotic response of GBM xenografts. In addition to that which we accomplish by implementing the research plan described herein, we anticipate that the resources that are developed and distributed in association with this project will allow other groups a better opportunity to achieve their own EFGR-related research objectives. These xenograft lines will, therefore assist other members of the research community in focusing a sizeable repertoire of approaches and disciplines on the consequences of this gene alteration, and to thoroughly investigate the clinical potential of therapies directed against Efg receptor.

描述：（由申请人提供）EGFR的扩增是在最常见和最恶性的原发性脑肿瘤，胶质母细胞瘤（GBM）中鉴定出的第一个基因改变。尽管有将近20年的GBM-EFGR研究，以及从相关研究中积累的大量信息，但很少努力开发一个体内系统，用于促进分子生物学和对GBM高度表达的EGF受体的分子生物学和治疗靶向的研究。该提案是为了解决这种缺陷，并使用此工作从这项工作中得出的模型来解决涉及GBM中EGFR扩增的基本问题。我们正在开发和表征维持EGFR扩增的可串行转移的GBM异种移植线，将用于实现以下特定目的：具体目标1：确定与通过EFGR扩增从GBM Xenograft从GBM Xenograft建立细胞系的分子和肿瘤生物学特性的变化。具体目标2：确认EGFR扩增与升高磷酸化之间体内关系的初步观察，并确定这种关系的分子和肿瘤生物学后果。具体目标3：关于EFGR扩增状态，确定和内向，EGF受体的小分子抑制剂对GBM异种移植物GBM的原位生长，浸润，血管化和凋亡反应的体内影响。除了实现本文所述的研究计划来实现的目标之外，我们预计与该项目共同开发和分发的资源将使其他团体有一个更好的机会来实现与EFGR相关的研究目标。因此，这些异种移植线将帮助研究界的其他成员将大量的方法和学科集中在该基因改变的后果上，并彻底研究针对EFG受体的疗法的临床潜力。