The overall objective of this translational research project is to develop a two pronged attack against high grade brain tumors, first, by specific molecular targeting of either the epidermal growth factor receptor (EGFR) or a mutant isoform of the receptor, EGFRvIII. However, since there is considerable variability in EGFR expression among malignant gliomas and within individual tumors themselves, this receptor alone cannot be the only target for gliomas in general or for all of the constituent cells of any individual tumor. Therefore, combinations of agents will be required. Accordingly, the second part of this attack will utilize two FDA approved, low molecular weight drugs that have been used clinically for boron neutron capture therapy (BNCT). The first is a boronophenylalanine or BPA, which is preferentially taken up by more metabolically active tumor cells, and the second is a blood-brain barrier permeable drug, sodium borocaptate (BSH). Following administration of the boron delivery agents, BNCT will be initiated at a point in time when there is an optimum tumor to normal brain boron ratio. To carry out these studies, we have developed two rat glioma models from the EGFR (-) F98 parental tumor, which has been transfected with either the gene encoding human """"""""wild type"""""""" EGFR or EGFRvIII. The F98EGFR expresses amplified wild type EGFR and the second, F98EGFRVIII, expresses an amplified mutant isoform of the receptor, EGFRvlII, which has a more restricted expression on human malignant gliomas. Each of these receptors is expressed with high density (>105 receptor sites) in the corresponding F98 transfectant. Targeting agents that already have been developed by us include heavily boronated EGF and a boronated monoclonal antibody, which recognizes EGFRvIII. Since systemic administration of high molecular weight agents has been ineffective in targeting brain tumors, a more efficient approach, convection-enhanced delivery, will be used. The most important question raised by any translational research project is its applicability to future clinical trials. The key question that we will answer is """"""""Can molecular targeting of EGFR (or EGFRvIII), combined with the second generation drugs BPA and BSH, produce a significant improvement in survival following BNCT compared to that which we have obtained with BSH and BPA in combination, using the F98EGFR and F98EGFRVIII glioma models?""""""""
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