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AZD3759, a BBB-penetrating EGFR inhibitor for the treatment of EGFR mutant NSCLC with CNS metastases

Cited 6 time in Web of Science Cited 54 time in Scopus
Authors
Yang, Zhenfan; Guo, Qiuli; Wang, Yingchun; Chen, Kan; Zhang, Lin; Cheng, Ziqiang; Xu, Yanping; Yin, Xiaolu; Bai, Yu; Rabbie, Sarit; Kim, Dong-Wan; Ahn, Myung-Ju; Yang, James Chih-Hsin; Zhang, Xiaolin
Issue Date
2016-12
Citation
Science Translational Medicine, Vol.8 No.368, p. 368ra172
Abstract
Non-small-cell lung cancer patients with activating mutations in epidermal growth factor receptor (EGFR) respond to EGFR tyrosine kinase inhibitor (TKI) treatment. Nevertheless, patients often develop central nervous system (CNS) metastases during treatment, even when their extracranial tumors are still under control. In the absence of effective options, much higher doses of EGFR TKIs have been attempted clinically, with the goal of achieving high enough drug concentrations within the CNS. Although limited tumor responses have been observed with this approach, the toxicities outside the CNS have been too high to tolerate. We report the discovery and early clinical development of AZD3759, a selective EGFR inhibitor that can fully penetrate the blood-brain barrier (BBB), with equal free concentrations in the blood, cerebrospinal fluid, and brain tissue. Treatment with AZD3759 causes tumor regression in subcutaneous xenograft, leptomeningeal metastasis (LM), and brain metastasis (BM) lung cancer models and prevents the development of BM in nude mice. An early clinical study in patients with BM and LM treated with AZD3759 confirms its BBB-penetrant properties and antitumor activities. Our data demonstrate the potential of AZD3759 for the treatment of BM and LM and support its further clinical evaluation in larger trials.
ISSN
1946-6234
URI
https://hdl.handle.net/10371/165294
DOI
https://doi.org/10.1126/scitranslmed.aag0976
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College of Medicine/School of Medicine (의과대학/대학원)Cancer Research Institute (암연구소)Journal Papers (저널논문_암연구소)
College of Medicine/School of Medicine (의과대학/대학원)Internal Medicine (내과학전공)Journal Papers (저널논문_내과학전공)
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