复发性胶质母细胞瘤的分子靶向治疗：当前及未来的靶点
Molecularly targeted therapies for recurrent glioblastoma: current and future targets.
作者信息
Lau Darryl, Magill Stephen T, Aghi Manish K
机构信息
Department of Neurological Surgery, University of California, San Francisco, California.
出版信息
Neurosurg Focus. 2014 Dec;37(6):E15. doi: 10.3171/2014.9.FOCUS14519.
OBJECT
Glioblastoma is the most aggressive and diffusely infiltrative primary brain tumor. Recurrence is expected and is extremely difficult to treat. Over the past decade, the accumulation of knowledge regarding the molecular and genetic profile of glioblastoma has led to numerous molecularly targeted therapies. This article aims to review the literature and highlight the mechanisms and efficacies of molecularly targeted therapies for recurrent glioblastoma.
METHODS
A systematic search was performed with the phrase "(name of particular agent) and glioblastoma" as a search term in PubMed to identify all articles published up until 2014 that included this phrase in the title and/or abstract. The references of systematic reviews were also reviewed for additional sources. The review included clinical studies that comprised at least 20 patients and reported results for the treatment of recurrent glioblastoma with molecular targeted therapies.
RESULTS
A total of 42 articles were included in this review. In the treatment of recurrent glioblastoma, various targeted therapies have been tested over the past 10-15 years. The targets of interest include epidermal growth factor receptor, vascular endothelial growth factor receptor, platelet-derived growth factor receptor, Ras pathway, protein kinase C, mammalian target of rapamycin, histone acetylation, and integrins. Unfortunately, the clinical responses to most available targeted therapies are modest at best. Radiographic responses generally range in the realm of 5%-20%. Progression-free survival at 6 months and overall survival were also modest with the majority of studies reporting a 10%-20% 6-month progression-free survival and 5- to 8-month overall survival. There have been several clinical trials evaluating the use of combination therapy for molecularly targeted treatments. In general, the outcomes for combination therapy tend to be superior to single-agent therapy, regardless of the specific agent studied.
CONCLUSIONS
Recurrent glioblastoma remains very difficult to treat, even with molecular targeted therapies and anticancer agents. The currently available targeted therapy regimens have poor to modest activity against recurrent glioblastoma. As newer agents are actively being developed, combination regimens have provided the most promising results for improving outcomes. Targeted therapies matched to molecular profiles of individual tumors are predicted to be a critical component necessary for improving efficacy in future trials.
目的
胶质母细胞瘤是最具侵袭性且弥漫浸润性的原发性脑肿瘤。复发难以避免且极难治疗。在过去十年中，关于胶质母细胞瘤分子和基因特征的知识积累催生了众多分子靶向疗法。本文旨在回顾相关文献并着重介绍复发性胶质母细胞瘤分子靶向疗法的作用机制及疗效。
方法
在PubMed中以“（特定药物名称）和胶质母细胞瘤”为检索词进行系统检索，以识别截至2014年发表的所有在标题和/或摘要中包含该检索词的文章。还查阅了系统评价的参考文献以获取更多来源。该综述纳入了至少有20例患者的临床研究，并报告了分子靶向疗法治疗复发性胶质母细胞瘤的结果。
结果
本综述共纳入42篇文章。在复发性胶质母细胞瘤的治疗中，过去10 - 15年里对多种靶向疗法进行了测试。感兴趣的靶点包括表皮生长因子受体、血管内皮生长因子受体、血小板衍生生长因子受体、Ras通路、蛋白激酶C、雷帕霉素靶蛋白、组蛋白乙酰化以及整合素。遗憾的是，大多数现有靶向疗法的临床反应充其量只能说是一般。影像学反应通常在5% - 20%的范围内。6个月无进展生存期和总生存期也较为一般，大多数研究报告6个月无进展生存期为10% - 20%，总生存期为5至8个月。有几项临床试验评估了分子靶向治疗联合疗法的应用。总体而言，无论所研究的具体药物如何，联合疗法的效果往往优于单药治疗。
结论
即使采用分子靶向疗法和抗癌药物，复发性胶质母细胞瘤仍然极难治疗。目前可用的靶向治疗方案对复发性胶质母细胞瘤的活性较差至一般。随着新药物的积极研发，联合治疗方案在改善治疗效果方面提供了最有前景的结果。与个体肿瘤分子特征相匹配的靶向疗法预计将是未来试验提高疗效所必需的关键组成部分。
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