Preclinical evaluation of targeted therapies for central nervous system metastases.

IF 4 3区 医学 Q2 CELL BIOLOGY
Disease Models & Mechanisms Pub Date : 2024-09-01 Epub Date: 2024-09-30 DOI:10.1242/dmm.050836
Alexander J Pfeil, Joshua D Hale, Tiger S Zhang, Kentaro Wakayama, Isao Miyazaki, Igor Odintsov, Romel Somwar
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引用次数: 0

Abstract

The central nervous system (CNS) represents a site of sanctuary for many metastatic tumors when systemic therapies that control the primary tumor cannot effectively penetrate intracranial lesions. Non-small cell lung cancers (NSCLCs) are the most likely of all neoplasms to metastasize to the brain, with up to 60% of patients developing CNS metastases during the disease process. Targeted therapies such as tyrosine kinase inhibitors (TKIs) have helped reduce lung cancer mortality but vary considerably in their capacity to control CNS metastases. The ability of these therapies to effectively target lesions in the CNS depends on several of their pharmacokinetic properties, including blood-brain barrier permeability, affinity for efflux transporters, and binding affinity for both plasma and brain tissue. Despite the existence of numerous preclinical models with which to characterize these properties, many targeted therapies have not been rigorously tested for CNS penetration during the discovery process, whereas some made it through preclinical testing despite poor brain penetration kinetics. Several TKIs have now been engineered with the characteristics of CNS-penetrant drugs, with clinical trials proving these efforts fruitful. This Review outlines the extent and variability of preclinical evidence for the efficacy of NSCLC-targeted therapies, which have been approved by the US Food and Drug Administration (FDA) or are in development, for treating CNS metastases, and how these data correlate with clinical outcomes.

中枢神经系统转移瘤靶向疗法的临床前评估。
当控制原发肿瘤的全身疗法无法有效穿透颅内病灶时,中枢神经系统(CNS)就成了许多转移性肿瘤的避难所。非小细胞肺癌(NSCLC)是所有肿瘤中最有可能向大脑转移的肿瘤,高达 60% 的患者在发病过程中会出现中枢神经系统转移。酪氨酸激酶抑制剂(TKIs)等靶向疗法有助于降低肺癌死亡率,但在控制中枢神经系统转移的能力方面却存在很大差异。这些疗法能否有效针对中枢神经系统的病变取决于其药代动力学特性,包括血脑屏障通透性、对外排转运体的亲和力以及与血浆和脑组织的结合亲和力。尽管有许多临床前模型可用于描述这些特性,但许多靶向治疗药物在发现过程中并未经过严格的中枢神经系统穿透测试,而有些药物尽管脑穿透动力学较差,但仍通过了临床前测试。现在,有几种 TKIs 已被设计为具有中枢神经系统穿透性的药物,临床试验证明这些努力卓有成效。本综述概述了已获美国食品药品管理局 (FDA) 批准或正在开发的 NSCLC 靶向疗法治疗中枢神经系统转移瘤的临床前疗效证据的范围和可变性,以及这些数据与临床结果的相关性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Disease Models & Mechanisms
Disease Models & Mechanisms 医学-病理学
CiteScore
6.60
自引率
7.00%
发文量
203
审稿时长
6-12 weeks
期刊介绍: Disease Models & Mechanisms (DMM) is an online Open Access journal focusing on the use of model systems to better understand, diagnose and treat human disease.
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