Preclinical evaluation of targeted therapies for central nervous system metastases Review
| Authors: | Pfeil, A. J.; Hale, J. D.; Zhang, T. S.; Wakayama, K.; Miyazaki, I.; Odintsov, I.; Somwar, R. |
| Review Title: | Preclinical evaluation of targeted therapies for central nervous system metastases |
| 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. © 2024. Published by The Company of Biologists Ltd. |
| Keywords: | review; nonhuman; systemic therapy; binding affinity; animal; metabolism; animals; protein kinase inhibitor; lung cancer; food and drug administration; drug effect; pathology; drug evaluation, preclinical; central nervous system tumor; central nervous system; central nervous system neoplasms; protein kinase inhibitors; blood brain barrier; blood-brain barrier; targeted therapy; drug therapy; non-small cell lung cancer; therapy; pharmacokinetics; non small cell lung cancer; central nervous system metastasis; molecularly targeted therapy; clinical outcome; molecular targeted therapy; brain damage; brain tissue; preclinical study; humans; human |
| Journal Title: | Disease Models & Mechanisms |
| Volume: | 17 |
| Issue: | 9 |
| ISSN: | 1754-8403 |
| Publisher: | Company of Biologists |
| Date Published: | 2024-09-01 |
| Start Page: | dmm050836 |
| Language: | English |
| DOI: | 10.1242/dmm.050836 |
| PUBMED: | 39344915 |
| PROVIDER: | scopus |
| PMCID: | PMC11463968 |
| DOI/URL: | |
| Notes: | Review -- MSK corresponding author is Romel Somwar -- Source: Scopus |
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