Targeted Gene Delivery Against Glioblastoma multiforme

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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.