Molecular Targeting of EGFR for the Treatment of Gliomas

描述(申请人提供)：这个翻译研究项目的总体目标是开发一种针对高级别脑瘤的双管齐下的攻击方法，首先，通过特定的分子靶向表皮生长因子受体(EGFR)或该受体的突变亚型EGFRvIII。然而，由于EGFR在恶性胶质瘤和个别肿瘤中的表达有相当大的差异，该受体本身并不是一般胶质瘤或任何个别肿瘤的所有组成细胞的唯一靶点。因此，将需要多个代理组合。因此，这次攻击的第二部分将使用FDA批准的两种低分子药物，这两种药物已在临床上用于硼中子俘获疗法(BNCT)。第一种是硼苯丙氨酸或BPA，它优先被代谢活性更高的肿瘤细胞摄取，第二种是血脑屏障渗透性药物，即硼碳酸钠(BSH)。在给药后，BNCT将在肿瘤与正常脑硼的最佳比例的时间点启动。为了进行这些研究，我们从EGFR(-)F98亲本肿瘤中建立了两个大鼠脑胶质瘤模型，该肿瘤已经转染了编码人类“野生型”EGFR或EGFRvIII的基因。F98EGFR表达扩增的野生型EGFR，第二种F98EGFRVIII表达该受体的扩增突变异构体EGFRvlII，其在人类恶性胶质瘤中的表达受到更多限制。这些受体中的每一个都在相应的F98转染体中以高密度(&gt；105个受体位点)表达。我们已经开发的靶向剂包括大量硼化的EGF和识别EGFRvIII的硼化单抗。由于全身给药在靶向脑肿瘤方面效果不佳，将使用一种更有效的方法，即对流增强递送。任何转化性研究项目提出的最重要的问题是它对未来临床试验的适用性。我们要回答的关键问题是“分子靶向EGFR(或EGFRvIII)，结合第二代药物BPA和BSH，与我们使用F98EGFR和F98EGFRVIII胶质瘤模型联合使用BSH和BPA获得的BNCT相比，能否显著改善BNCT后的存活率？”

DESCRIPTION (provided by applicant): 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?"