Primary brain tumors cause over 12,000 deaths each year in the United states alone. Existing therapies are largely ineffective. Gene therapy is receiving considerable attention as a method of delivering therapeutic proteins to tumors. The presence of proliferating endothelial cells (ECs) in brain tumors suggested to us that ECs could serve as versatile platforms for delivering gene products to brain tumors. This study will establish optimal conditions for the transplantation of genetically modified ECs to brain tumors, and determine if endothelial-based gene delivery can be used to inhibit glioma growth. We have already established the methodology to express novel genes in cultured ECs and have shown that ECs survive implantation to rat gliomas and human glioma xenographs. These engrafted ECs proliferate and integrate with the tumor vasculature. We have generated endothelial cell lines to be used for in vivo studies that secrete either high levels of interleukin-2 (IL-2), a cytokine with anti-tumor activity, or fibroblast growth factor (FGF), an endothelial mitogen that stimulates endothelial proliferation in vivo. Our promising results using endothelial cells that secrete IL-2 will be refined and endothelial-derived therapeutic proteins.
Aim 2 will determine if endothelial-based gene delivery can inhibit glioma growth in vivo. Our promising results using endothelial cells that secrete IL-2 will be refined and endothelial cells that deliver other cytokines with anti- tumor properties (interleukin-4, tumor necrosis factor) will be examined. Transgene expression by cultured and engrafted ECs will be quantified using immunologic, biochemical, activity, and molecular biological assays. Effects of delivering these factors by EC implantation on tumor growth and survival of animals bearing intracranial tumors will be determined. Our findings will establish the feasibility of EC-based brain tumor gene therapy for brain tumors and provide reagents and protocols for EC-based therapy for other CNS disorders.
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