Targeted Gene Delivery Against Glioblastoma multiforme

针对多形性胶质母细胞瘤的靶向基因递送

• 批准号: 6936404
• 负责人: Michael Lim
• 金额: $ 5.35万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6936404
• 关键词: angiogenesis; biotechnology; cell line; confocal scanning microscopy; fibroblast growth factor; gene expression; gene therapy; glioblastoma multiforme; green fluorescent proteins; integrins; laboratory mouse; laboratory rat; magnetic resonance imaging; nanotechnology; neoplasm /cancer blood supply; particle; postdoctoral investigator; protein localization; vascular endothelial growth factors

DESCRIPTION (provided by applicant): Glioblastoma multiforme (GBM) is a malignant brain tumor whose development depends on angiogenesis. We propose to investigate a novel antiangiogenic strategy. It targets the integrin avb3, a cell surface protein markedly expressed on endothelial cells involved in angiogenesis of tumors such as GBMs. We have created a cationic nanoparticle (NP) containing an avb3 ligand and a plasmid for a mutant version of raf, ATP/M-Raf, a central component of the Ras-Raf-MEK-ERK kinase pathways in angiogenesis. ATPM-Raf, acts in a dominant negative fashion to suppress angiogenesis. The construct injected intravenously resulted in destruction of tumor vasculature, apoptosis of tumor cells adjacent to vessels, improved tumor control and increased survival of a rodent melanoma model. Our central hypothesis is that inhibiting angiogenesis will improve the survival of patients with GBMs. Our aims for investigating this hypothesis are: 1. Establish the presence of avb3 on endothelial cells of our rat glioma model, RT2. 2. Establish localization of avb3-NP for endothelial cells of the RT2 tumor. 3. Demonstrate tumor control and improved rat survival in the RT2 model following treatment with avb3-NP affixed to ATP/m-Raf.

描述(申请人提供)：多形性胶质母细胞瘤(GBM)是一种恶性脑瘤，其发展依赖于血管生成。我们建议研究一种新的抗血管生成策略。它针对整合素avb3，这是一种在内皮细胞上显著表达的细胞表面蛋白，参与了肿瘤的血管生成，如基底膜。我们已经创造了一种阳离子纳米颗粒(NP)，它包含一个avb3配体和一个突变版本的RAF，ATP/M-Raf，它是血管生成中Ras-Raf-MEK-ERK通路的中心成分。ATPM-Raf以显性负性方式抑制血管生成。静脉注射该构建体导致肿瘤血管的破坏，邻近血管的肿瘤细胞凋亡，改善了肿瘤控制，提高了啮齿动物黑色素瘤模型的存活率。我们的中心假设是，抑制血管生成将提高GBMS患者的存活率。我们研究这一假说的目的是：1.建立我们的大鼠脑胶质瘤模型RT2的内皮细胞上存在avb3。2.建立rt2肿瘤血管内皮细胞avb3-NP的定位。3.在rt2模型中，通过将avb3-NP固定在ATP/m-Raf上，证明肿瘤得到了控制并提高了大鼠的存活率。

项目成果

Characterization of the integrin alpha v beta3 in arteriovenous malformations and cavernous malformations.

动静脉畸形和海绵状血管瘤中整合素 α v beta3 的表征。

• DOI: 10.1159/000086123
• 发表时间: 2005
• 期刊: Cerebrovascular diseases (Basel, Switzerland)
• 作者: Lim,Michael;Haddix,Terri;Harsh,GriffithR;Vogel,Hannes;Steinberg,GaryK;Guccione,Samira
• 通讯作者: Guccione,Samira