Touat M, Idbaih A, Sanson M, Ligon K L
Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, Paris.
Gustave Roussy, Université Paris-Saclay, Département d'Innovation Thérapeutique et d'Essais Précoces (DITEP), Villejuif.
Ann Oncol. 2017 Jul 1;28(7):1457-1472. doi: 10.1093/annonc/mdx106.
Glioblastoma (WHO grade IV astrocytoma) is the most frequent primary brain tumor in adults, representing a highly heterogeneous group of neoplasms that are among the most aggressive and challenging cancers to treat. An improved understanding of the molecular pathways that drive malignancy in glioblastoma has led to the development of various biomarkers and the evaluation of several agents specifically targeting tumor cells and the tumor microenvironment. A number of rational approaches are being investigated, including therapies targeting tumor growth factor receptors and downstream pathways, cell cycle and epigenetic regulation, angiogenesis and antitumor immune response. Moreover, recent identification and validation of prognostic and predictive biomarkers have allowed implementation of modern trial designs based on matching molecular features of tumors to targeted therapeutics. However, while occasional targeted therapy responses have been documented in patients, to date no targeted therapy has been formally validated as effective in clinical trials. The lack of knowledge about relevant molecular drivers in vivo combined with a lack of highly bioactive and brain penetrant-targeted therapies remain significant challenges. In this article, we review the most promising biological insights that have opened the way for the development of targeted therapies in glioblastoma, and examine recent data from clinical trials evaluating targeted therapies and immunotherapies. We discuss challenges and opportunities for the development of these agents in glioblastoma.
胶质母细胞瘤（世界卫生组织IV级星形细胞瘤）是成人中最常见的原发性脑肿瘤，是一组高度异质性的肿瘤，属于最难治疗的侵袭性癌症。对驱动胶质母细胞瘤恶性进展的分子途径的深入了解，已促使多种生物标志物的开发，并对几种专门针对肿瘤细胞和肿瘤微环境的药物进行了评估。目前正在研究多种合理的方法，包括针对肿瘤生长因子受体及其下游途径、细胞周期和表观遗传调控、血管生成以及抗肿瘤免疫反应的疗法。此外，最近对预后和预测性生物标志物的鉴定和验证，使得基于肿瘤分子特征与靶向治疗相匹配的现代试验设计得以实施。然而，尽管有文献记载患者偶尔会出现靶向治疗反应，但迄今为止，尚无靶向治疗在临床试验中被正式验证为有效。体内相关分子驱动因素的知识匮乏，加上缺乏高生物活性且能穿透血脑屏障的靶向治疗方法，仍然是重大挑战。在本文中，我们回顾了为胶质母细胞瘤靶向治疗发展开辟道路的最有前景的生物学见解，并审视了评估靶向治疗和免疫治疗的临床试验的最新数据。我们讨论了这些药物在胶质母细胞瘤治疗中面临的挑战和机遇。
