Epidermal growth factor receptor inhibitors in neuro-oncology: Hopes and disappointments
Epidermal growth factor receptor inhibitors in neuro-oncology: Hopes and disappointments
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DOI：
10.1158/1078-0432.ccr-07-1810
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发表时间：
2008-02-15
影响因子：
11.5
通讯作者：
Stupp, Roger
中科院分区：
文献类型：
--
作者：
Brandes, Alba A.;Franceschi, Enrico;Stupp, Roger
尽管在过去的二十年里在诊断和治疗方面取得了进展，但高级别胶质瘤仍然是不可治愈的肿瘤。此外，在辅助治疗失败后，很少有积极的治疗方法可用。因此，在这种情况下，已经研究了新的药剂，例如针对特定分子靶标的新的化疗化合物和抗癌剂。表皮生长因子受体（EGFR）是一个有趣的目标，在高级别胶质瘤，因为它经常过度表达，由于扩增的EGFR基因。吉非替尼和厄洛替尼作为ATP模拟剂，与细胞质ATP口袋结构域结合并阻断受体磷酸化，从而阻断EGFR介导的下游途径活化。这些药物已经在几项治疗复发性高级别胶质瘤的临床试验中进行了评估，结果截然不同。回顾性相关分析产生了过多的EGFR酪氨酸激酶抑制剂活性的推定预测因素。关于EGFR抑制剂的第一代研究尚未发现这些药物在高级别胶质瘤中具有显着活性。此外，尚未确定明确的分子或临床预测因子。与其他靶向药物一样，需要使用特定标准和标准化方法进行前瞻性试验来评估组织生物标志物，以找到高级别胶质瘤患者EGFR抑制剂活性的预测因子。
Despite advances in diagnosis and treatment made over the past two decades, high-grade gliomas are still incurable neoplasms. Moreover, after failing adjuvant therapy, few active treatments are available. In this setting, novel agents, such as new chemotherapy compounds and anticancer agents against specific molecular targets, have therefore been investigated. Epidermal growth factor receptor (EGFR) is an intriguing target in high-grade gliomas because it is frequently overexpressed due to amplification of the EGFR gene. Gefitinib and erlotinib act as ATP mimetic agents, binding to the cytoplasmic ATP pocket domain and blocking receptor phosphorylations and, thereby, EGFR-mediated activation of downstream pathways. These drugs have been evaluated in several clinical trials treating recurrent high-grade gliomas with contrasting results. Retrospective correlative analyses generated a plethora of putative predictive factors of activity of EGFR tyrosine kinase inhibitors. The first generations of studies on EGFR inhibitors have not found significant activity of these agents in high-grade gliomas. Furthermore, no clear molecular or clinical predictors have been identified. As with other targeted agents, prospective trials using specific criteria and standardized methods to evaluate tissue biomarkers are required to find predictors of EGFR inhibitors activity in high-grade glioma patients.