1. Preclinical evaluation of targeted therapies for central nervous system metastases.
- Author
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Pfeil AJ, Hale JD, Zhang TS, Wakayama K, Miyazaki I, Odintsov I, and Somwar R
- Subjects
- Humans, Animals, Drug Evaluation, Preclinical, Protein Kinase Inhibitors therapeutic use, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors pharmacokinetics, Blood-Brain Barrier metabolism, Blood-Brain Barrier drug effects, Blood-Brain Barrier pathology, Central Nervous System Neoplasms drug therapy, Central Nervous System Neoplasms pathology, Central Nervous System Neoplasms secondary, Central Nervous System Neoplasms metabolism, Molecular Targeted Therapy
- 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., Competing Interests: Competing interests A.J.P., J.D.H., T.S.Z. and I.O. report no potential conflicts of interest. K.W. and I.M. are employees of Taiho Pharmaceutical Company. R.S. has received research grants from Helsinn Healthcare SA, Loxo Oncology, Elevation Oncology and Merus, all unrelated to the current article., (© 2024. Published by The Company of Biologists Ltd.)
- Published
- 2024
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