Molecular Targeting of EGFR for the Treatment of Gliomas

描述（由申请人提供）：该转化研究项目的总体目标是开发针对高级别脑肿瘤的双管齐下的攻击，首先，通过特异性分子靶向表皮生长因子受体（EGFR）或受体的突变亚型EGFRvIII。 然而，由于EGFR在恶性胶质瘤之间和个体肿瘤本身内的表达存在相当大的差异，因此这种受体单独不能成为一般胶质瘤或任何个体肿瘤的所有组成细胞的唯一靶标。 因此，将需要药剂的组合。 因此，第二部分的攻击将利用两个FDA批准的低分子量药物，已用于硼中子捕获治疗（BNCT）的临床。 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吸收，第二种是血脑屏障渗透性药物，硼帽酸钠（BSH）。 在施用硼递送剂之后，BNCT将在肿瘤与正常脑硼比率最佳的时间点开始。 为了进行这些研究，我们从EGFR（-）F98亲本肿瘤中开发了两种大鼠神经胶质瘤模型，所述亲本肿瘤已经转染了编码人“野生型”EGFR或EGFRvIII的基因。 F98 EGFR表达扩增的野生型EGFR，第二个F98 EGFRVIII表达受体的扩增的突变体同种型EGFRvIII，其在人恶性神经胶质瘤中具有更受限制的表达。 这些受体中的每一种在相应的F98转染子中以高密度（>105个受体位点）表达。 我们已经开发的靶向药物包括重硼化EGF和识别EGFRvIII的硼化单克隆抗体。 由于高分子量药物的全身给药在靶向脑肿瘤方面无效，因此将使用更有效的方法，即对流增强递送。 任何转化研究项目提出的最重要的问题是其对未来临床试验的适用性。 我们将回答的关键问题是“与我们使用F98 EGFR和F98 EGFRVIII胶质瘤模型使用BSH和BPA组合获得的结果相比，EGFR（或EGFRvIII）的分子靶向与第二代药物BPA和BSH组合是否可以显著改善BNCT后的生存率？"

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?"