Xenograft Model for Studying Amplified EGFR in GBM

描述：(申请人提供)EGFR扩增是在最常见和最恶性的原发脑瘤-胶质母细胞瘤(GBM)中发现的第一个基因改变。尽管近20年的GBM-EFGR研究和相关研究积累了大量的信息，但很少有人致力于体内系统的开发，以促进EGFR扩增的GBM中高表达的EGF受体的分子生物学和治疗靶向的研究。本建议的目的是解决这一不足，并使用从这项工作中得出的模型(S)来解决涉及GBM中EGFR扩增的基本问题。我们正在开发和鉴定的可连续移植的、保持EGFR扩增的GBM异种移植系的模型将用于实现以下特定目标：特定目标1：确定与建立具有EFGR扩增的GBM异种移植细胞系相关的分子和肿瘤生物学特性的变化。具体目标2：确认在体内初步观察到EGFR扩增和PLCy磷酸化升高之间的关系，并确定这种关系的分子和肿瘤生物学后果。具体目标3：针对EFGR扩增状态，确定和解释EGF受体小分子抑制剂对GBM异种移植的原位生长、侵袭、血管形成和凋亡反应的体内影响。除了我们通过实施这里描述的研究计划所实现的目标外，我们预计，与该项目相关的开发和分配的资源将使其他小组有更好的机会实现他们自己的EFGR相关研究目标。因此，这些异种移植系将帮助研究界的其他成员将相当大的方法和学科集中在这种基因改变的后果上，并彻底调查针对EFG受体的治疗的临床潜力。

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.