Department of Radiation Medicine, North Shore-Long Island Jewish Health System, Lake Success, NY, USA.
Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA.
Lancet Oncol. 2015 Oct;16(13):e510-21. doi: 10.1016/S1470-2045(15)00013-3.
The incidence of brain metastases has increased as a result of improved systemic control and advances in imaging. However, development of novel therapeutics with CNS activity has not advanced at the same rate. Research on molecular markers has revealed many potential targets for antineoplastic agents, and a particularly important aberration is translocation in the ALK gene, identified in non-small-cell lung cancer (NSCLC). ALK inhibitors have shown systemic efficacy against ALK-rearranged NSCLC in many clinical trials, but the effectiveness of crizotinib in CNS disease is limited by poor blood-brain barrier penetration and acquired drug resistance. In this Review, we discuss potential pathways to target ALK-rearranged brain metastases, including next generation ALK inhibitors with greater CNS penetration and mechanisms to overcome resistance. Other important mechanisms to control CNS disease include targeting pathways downstream of ALK phosphorylation, increasing the permeability of the blood-brain barrier, modifying the tumour microenvironment, and adding concurrent radiotherapy.
由于全身控制的改善和成像技术的进步，脑转移的发病率有所增加。然而，具有中枢神经系统活性的新型治疗药物的发展并没有以相同的速度推进。对分子标志物的研究揭示了许多抗肿瘤药物的潜在靶点，其中一个特别重要的异常是在非小细胞肺癌（NSCLC）中发现的 ALK 基因易位。ALK 抑制剂在许多临床试验中显示出对 ALK 重排的 NSCLC 的全身疗效，但克唑替尼在中枢神经系统疾病中的疗效受到血脑屏障通透性差和获得性耐药的限制。在这篇综述中，我们讨论了针对 ALK 重排脑转移的潜在途径，包括具有更高中枢神经系统穿透力的下一代 ALK 抑制剂和克服耐药性的机制。控制中枢神经系统疾病的其他重要机制包括靶向 ALK 磷酸化下游途径、增加血脑屏障通透性、修饰肿瘤微环境以及联合放疗。
