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Dual endothelin receptor inhibition enhances T-DM1 efficacy in brain metastases from HER2-positive breast cancer

The effective treatment of cerebral metastases from HER2-positive breast cancer remains an unmet need. Recent studies indicate that activated astrocytes and brain endothelial cells exert chemoprotective effects on cancer cells through direct physical interaction. Here we report that the endothelin a...

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Autores principales: Askoxylakis, Vasileios, Ferraro, Gino B., Badeaux, Mark, Kodack, David P., Kirst, Isabelle, Shankaraiah, Ram C., Wong, Christina S. F., Duda, Dan G., Fukumura, Dai, Jain, Rakesh K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6333771/
https://www.ncbi.nlm.nih.gov/pubmed/30675514
http://dx.doi.org/10.1038/s41523-018-0100-8
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author Askoxylakis, Vasileios
Ferraro, Gino B.
Badeaux, Mark
Kodack, David P.
Kirst, Isabelle
Shankaraiah, Ram C.
Wong, Christina S. F.
Duda, Dan G.
Fukumura, Dai
Jain, Rakesh K.
author_facet Askoxylakis, Vasileios
Ferraro, Gino B.
Badeaux, Mark
Kodack, David P.
Kirst, Isabelle
Shankaraiah, Ram C.
Wong, Christina S. F.
Duda, Dan G.
Fukumura, Dai
Jain, Rakesh K.
author_sort Askoxylakis, Vasileios
collection PubMed
description The effective treatment of cerebral metastases from HER2-positive breast cancer remains an unmet need. Recent studies indicate that activated astrocytes and brain endothelial cells exert chemoprotective effects on cancer cells through direct physical interaction. Here we report that the endothelin axis mediates protection of HER2-amplified brain metastatic breast cancers to the anti-HER2 antibody–drug conjugate ado-trastuzumab emtansine (T-DM1). Macitentan, a dual inhibitor of endothelin receptors A and B, improves the efficacy of T-DM1 against breast cancers grown in the brain. We show that direct contact of brain stroma with cancer cells is required for protection to T-DM1. Our data suggest that targeting the endothelin axis may be beneficial when anti-signaling agent and cytotoxic agent are combined. These findings may contribute to the development of therapeutic approaches with enhanced efficacy in the brain microenvironment.
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spelling pubmed-63337712019-01-23 Dual endothelin receptor inhibition enhances T-DM1 efficacy in brain metastases from HER2-positive breast cancer Askoxylakis, Vasileios Ferraro, Gino B. Badeaux, Mark Kodack, David P. Kirst, Isabelle Shankaraiah, Ram C. Wong, Christina S. F. Duda, Dan G. Fukumura, Dai Jain, Rakesh K. NPJ Breast Cancer Brief Communication The effective treatment of cerebral metastases from HER2-positive breast cancer remains an unmet need. Recent studies indicate that activated astrocytes and brain endothelial cells exert chemoprotective effects on cancer cells through direct physical interaction. Here we report that the endothelin axis mediates protection of HER2-amplified brain metastatic breast cancers to the anti-HER2 antibody–drug conjugate ado-trastuzumab emtansine (T-DM1). Macitentan, a dual inhibitor of endothelin receptors A and B, improves the efficacy of T-DM1 against breast cancers grown in the brain. We show that direct contact of brain stroma with cancer cells is required for protection to T-DM1. Our data suggest that targeting the endothelin axis may be beneficial when anti-signaling agent and cytotoxic agent are combined. These findings may contribute to the development of therapeutic approaches with enhanced efficacy in the brain microenvironment. Nature Publishing Group UK 2019-01-15 /pmc/articles/PMC6333771/ /pubmed/30675514 http://dx.doi.org/10.1038/s41523-018-0100-8 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Brief Communication
Askoxylakis, Vasileios
Ferraro, Gino B.
Badeaux, Mark
Kodack, David P.
Kirst, Isabelle
Shankaraiah, Ram C.
Wong, Christina S. F.
Duda, Dan G.
Fukumura, Dai
Jain, Rakesh K.
Dual endothelin receptor inhibition enhances T-DM1 efficacy in brain metastases from HER2-positive breast cancer
title Dual endothelin receptor inhibition enhances T-DM1 efficacy in brain metastases from HER2-positive breast cancer
title_full Dual endothelin receptor inhibition enhances T-DM1 efficacy in brain metastases from HER2-positive breast cancer
title_fullStr Dual endothelin receptor inhibition enhances T-DM1 efficacy in brain metastases from HER2-positive breast cancer
title_full_unstemmed Dual endothelin receptor inhibition enhances T-DM1 efficacy in brain metastases from HER2-positive breast cancer
title_short Dual endothelin receptor inhibition enhances T-DM1 efficacy in brain metastases from HER2-positive breast cancer
title_sort dual endothelin receptor inhibition enhances t-dm1 efficacy in brain metastases from her2-positive breast cancer
topic Brief Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6333771/
https://www.ncbi.nlm.nih.gov/pubmed/30675514
http://dx.doi.org/10.1038/s41523-018-0100-8
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