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A brain-penetrant microtubule-targeting agent that disrupts hallmarks of glioma tumorigenesis
BACKGROUND: Glioma is sensitive to microtubule-targeting agents (MTAs), but most MTAs do not cross the blood brain barrier (BBB). To address this limitation, we developed the new chemical entity, ST-401, a brain-penetrant MTA. METHODS: Synthesis of ST-401. Measures of MT assembly and dynamics. Cell...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7813200/ https://www.ncbi.nlm.nih.gov/pubmed/33506204 http://dx.doi.org/10.1093/noajnl/vdaa165 |
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author | Horne, Eric A Diaz, Philippe Cimino, Patrick J Jung, Erik Xu, Cong Hamel, Ernest Wagenbach, Michael Kumasaka, Debra Wageling, Nicholas B Azorín, Daniel D Winkler, Frank Wordeman, Linda G Holland, Eric C Stella, Nephi |
author_facet | Horne, Eric A Diaz, Philippe Cimino, Patrick J Jung, Erik Xu, Cong Hamel, Ernest Wagenbach, Michael Kumasaka, Debra Wageling, Nicholas B Azorín, Daniel D Winkler, Frank Wordeman, Linda G Holland, Eric C Stella, Nephi |
author_sort | Horne, Eric A |
collection | PubMed |
description | BACKGROUND: Glioma is sensitive to microtubule-targeting agents (MTAs), but most MTAs do not cross the blood brain barrier (BBB). To address this limitation, we developed the new chemical entity, ST-401, a brain-penetrant MTA. METHODS: Synthesis of ST-401. Measures of MT assembly and dynamics. Cell proliferation and viability of patient-derived (PD) glioma in culture. Measure of tumor microtube (TM) parameters using immunofluorescence analysis and machine learning-based workflow. Pharmacokinetics (PK) and experimental toxicity in mice. In vivo antitumor activity in the RCAS/tv-a PDGFB-driven glioma (PDGFB-glioma) mouse model. RESULTS: We discovered that ST-401 disrupts microtubule (MT) function through gentle and reverisible reduction in MT assembly that triggers mitotic delay and cell death in interphase. ST-401 inhibits the formation of TMs, MT-rich structures that connect glioma to a network that promotes resistance to DNA damage. PK analysis of ST-401 in mice shows brain penetration reaching antitumor concentrations, and in vivo testing of ST-401 in a xenograft flank tumor mouse model demonstrates significant antitumor activity and no over toxicity in mice. In the PDGFB-glioma mouse model, ST-401 enhances the therapeutic efficacies of temozolomide (TMZ) and radiation therapy (RT). CONCLUSION: Our study identifies hallmarks of glioma tumorigenesis that are sensitive to MTAs and reports ST-401 as a promising chemical scaffold to develop brain-penetrant MTAs. |
format | Online Article Text |
id | pubmed-7813200 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-78132002021-01-26 A brain-penetrant microtubule-targeting agent that disrupts hallmarks of glioma tumorigenesis Horne, Eric A Diaz, Philippe Cimino, Patrick J Jung, Erik Xu, Cong Hamel, Ernest Wagenbach, Michael Kumasaka, Debra Wageling, Nicholas B Azorín, Daniel D Winkler, Frank Wordeman, Linda G Holland, Eric C Stella, Nephi Neurooncol Adv Basic and Translational Investigations BACKGROUND: Glioma is sensitive to microtubule-targeting agents (MTAs), but most MTAs do not cross the blood brain barrier (BBB). To address this limitation, we developed the new chemical entity, ST-401, a brain-penetrant MTA. METHODS: Synthesis of ST-401. Measures of MT assembly and dynamics. Cell proliferation and viability of patient-derived (PD) glioma in culture. Measure of tumor microtube (TM) parameters using immunofluorescence analysis and machine learning-based workflow. Pharmacokinetics (PK) and experimental toxicity in mice. In vivo antitumor activity in the RCAS/tv-a PDGFB-driven glioma (PDGFB-glioma) mouse model. RESULTS: We discovered that ST-401 disrupts microtubule (MT) function through gentle and reverisible reduction in MT assembly that triggers mitotic delay and cell death in interphase. ST-401 inhibits the formation of TMs, MT-rich structures that connect glioma to a network that promotes resistance to DNA damage. PK analysis of ST-401 in mice shows brain penetration reaching antitumor concentrations, and in vivo testing of ST-401 in a xenograft flank tumor mouse model demonstrates significant antitumor activity and no over toxicity in mice. In the PDGFB-glioma mouse model, ST-401 enhances the therapeutic efficacies of temozolomide (TMZ) and radiation therapy (RT). CONCLUSION: Our study identifies hallmarks of glioma tumorigenesis that are sensitive to MTAs and reports ST-401 as a promising chemical scaffold to develop brain-penetrant MTAs. Oxford University Press 2020-12-03 /pmc/articles/PMC7813200/ /pubmed/33506204 http://dx.doi.org/10.1093/noajnl/vdaa165 Text en © The Author(s) 2020. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Basic and Translational Investigations Horne, Eric A Diaz, Philippe Cimino, Patrick J Jung, Erik Xu, Cong Hamel, Ernest Wagenbach, Michael Kumasaka, Debra Wageling, Nicholas B Azorín, Daniel D Winkler, Frank Wordeman, Linda G Holland, Eric C Stella, Nephi A brain-penetrant microtubule-targeting agent that disrupts hallmarks of glioma tumorigenesis |
title | A brain-penetrant microtubule-targeting agent that disrupts hallmarks of glioma tumorigenesis |
title_full | A brain-penetrant microtubule-targeting agent that disrupts hallmarks of glioma tumorigenesis |
title_fullStr | A brain-penetrant microtubule-targeting agent that disrupts hallmarks of glioma tumorigenesis |
title_full_unstemmed | A brain-penetrant microtubule-targeting agent that disrupts hallmarks of glioma tumorigenesis |
title_short | A brain-penetrant microtubule-targeting agent that disrupts hallmarks of glioma tumorigenesis |
title_sort | brain-penetrant microtubule-targeting agent that disrupts hallmarks of glioma tumorigenesis |
topic | Basic and Translational Investigations |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7813200/ https://www.ncbi.nlm.nih.gov/pubmed/33506204 http://dx.doi.org/10.1093/noajnl/vdaa165 |
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