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Preclinical characterization of tyrosine kinase inhibitor-based targeted therapies for neuroendocrine thyroid cancer
Medullary thyroid carcinoma (MTC) is a slow growing neuroendocrine (NE) tumor for which few treatment options are available. Its incidence is rising and mortality rates have remained unchanged for decades. Increasing the repertoire of available treatments is thus crucial to manage MTC progression. S...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6340867/ https://www.ncbi.nlm.nih.gov/pubmed/30701022 http://dx.doi.org/10.18632/oncotarget.26480 |
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author | Pozo, Karine Zahler, Stefan Ishimatsu, Keisuke Carter, Angela M. Telange, Rahul Tan, Chunfeng Wang, Shuaijun Pfragner, Roswitha Fujimoto, Junya Grubbs, Elizabeth Gardner Takahashi, Masaya Oltmann, Sarah C. Bibb, James A. |
author_facet | Pozo, Karine Zahler, Stefan Ishimatsu, Keisuke Carter, Angela M. Telange, Rahul Tan, Chunfeng Wang, Shuaijun Pfragner, Roswitha Fujimoto, Junya Grubbs, Elizabeth Gardner Takahashi, Masaya Oltmann, Sarah C. Bibb, James A. |
author_sort | Pozo, Karine |
collection | PubMed |
description | Medullary thyroid carcinoma (MTC) is a slow growing neuroendocrine (NE) tumor for which few treatment options are available. Its incidence is rising and mortality rates have remained unchanged for decades. Increasing the repertoire of available treatments is thus crucial to manage MTC progression. Scarcity of patient samples and of relevant animal models are two challenges that have limited the development of effective non-surgical treatments. Here we use a clinically accurate mouse model of MTC to assess the effects and mode of action of the tyrosine kinase inhibitor (TKI) Vandetanib, one of only two drugs currently available to treat MTC. Effects on tumor progression, histopathology, and tumorigenic signaling were evaluated. Vandetanib blocked MTC growth through an anti-angiogenic mechanism. Furthermore, Vandetanib had an apparent anti-angiogenic effect in a patient MTC sample. Vandetanib displayed minimal anti-proliferative effects in vivo and in human and mouse MTC tumor-derived cells. Based on these results, we evaluated the second-generation TKI, Nintedanib, alone and in combination with the histone deacetylase (HDAC) inhibitor, Romidepsin, as potential alternative treatments to Vandetanib. Nintedanib showed an anti-angiogenic effect while Romidepsin decreased proliferation. Mechanistically, TKIs attenuated RET-, VEGFR2- and PI3K/AKT/FOXO signaling cascades. Nintedanib alone or in combination with Romidepsin, but not Vandetanib, inhibited mTOR signaling suggesting Nintedanib may have broader anti-cancer applicability. These findings validate the MTC mouse model as a clinically relevant platform for preclinical drug testing and reveal the modes of action and limitations of TKI therapies. |
format | Online Article Text |
id | pubmed-6340867 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-63408672019-01-30 Preclinical characterization of tyrosine kinase inhibitor-based targeted therapies for neuroendocrine thyroid cancer Pozo, Karine Zahler, Stefan Ishimatsu, Keisuke Carter, Angela M. Telange, Rahul Tan, Chunfeng Wang, Shuaijun Pfragner, Roswitha Fujimoto, Junya Grubbs, Elizabeth Gardner Takahashi, Masaya Oltmann, Sarah C. Bibb, James A. Oncotarget Research Paper Medullary thyroid carcinoma (MTC) is a slow growing neuroendocrine (NE) tumor for which few treatment options are available. Its incidence is rising and mortality rates have remained unchanged for decades. Increasing the repertoire of available treatments is thus crucial to manage MTC progression. Scarcity of patient samples and of relevant animal models are two challenges that have limited the development of effective non-surgical treatments. Here we use a clinically accurate mouse model of MTC to assess the effects and mode of action of the tyrosine kinase inhibitor (TKI) Vandetanib, one of only two drugs currently available to treat MTC. Effects on tumor progression, histopathology, and tumorigenic signaling were evaluated. Vandetanib blocked MTC growth through an anti-angiogenic mechanism. Furthermore, Vandetanib had an apparent anti-angiogenic effect in a patient MTC sample. Vandetanib displayed minimal anti-proliferative effects in vivo and in human and mouse MTC tumor-derived cells. Based on these results, we evaluated the second-generation TKI, Nintedanib, alone and in combination with the histone deacetylase (HDAC) inhibitor, Romidepsin, as potential alternative treatments to Vandetanib. Nintedanib showed an anti-angiogenic effect while Romidepsin decreased proliferation. Mechanistically, TKIs attenuated RET-, VEGFR2- and PI3K/AKT/FOXO signaling cascades. Nintedanib alone or in combination with Romidepsin, but not Vandetanib, inhibited mTOR signaling suggesting Nintedanib may have broader anti-cancer applicability. These findings validate the MTC mouse model as a clinically relevant platform for preclinical drug testing and reveal the modes of action and limitations of TKI therapies. Impact Journals LLC 2018-12-28 /pmc/articles/PMC6340867/ /pubmed/30701022 http://dx.doi.org/10.18632/oncotarget.26480 Text en Copyright: © 2018 Pozo et al. http://creativecommons.org/licenses/by/3.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) (CC-BY), which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Research Paper Pozo, Karine Zahler, Stefan Ishimatsu, Keisuke Carter, Angela M. Telange, Rahul Tan, Chunfeng Wang, Shuaijun Pfragner, Roswitha Fujimoto, Junya Grubbs, Elizabeth Gardner Takahashi, Masaya Oltmann, Sarah C. Bibb, James A. Preclinical characterization of tyrosine kinase inhibitor-based targeted therapies for neuroendocrine thyroid cancer |
title | Preclinical characterization of tyrosine kinase inhibitor-based targeted therapies for neuroendocrine thyroid cancer |
title_full | Preclinical characterization of tyrosine kinase inhibitor-based targeted therapies for neuroendocrine thyroid cancer |
title_fullStr | Preclinical characterization of tyrosine kinase inhibitor-based targeted therapies for neuroendocrine thyroid cancer |
title_full_unstemmed | Preclinical characterization of tyrosine kinase inhibitor-based targeted therapies for neuroendocrine thyroid cancer |
title_short | Preclinical characterization of tyrosine kinase inhibitor-based targeted therapies for neuroendocrine thyroid cancer |
title_sort | preclinical characterization of tyrosine kinase inhibitor-based targeted therapies for neuroendocrine thyroid cancer |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6340867/ https://www.ncbi.nlm.nih.gov/pubmed/30701022 http://dx.doi.org/10.18632/oncotarget.26480 |
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