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Plocabulin, a novel tubulin inhibitor, has potent antitumor activity in patient-derived xenograft models of gastrointestinal stromal tumors

The majority of patients with gastrointestinal stromal tumors (GIST) eventually become resistant with time due to secondary mutations in the driver receptor tyrosine kinase. Novel treatments that do not target these receptors may therefore be preferable. For the first time, we evaluated a tubulin in...

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Autores principales: Wang, Yannick, Wozniak, Agnieszka, Wellens, Jasmien, Gebreyohannes, Yemarshet K., Guillén, Maria Jose, Avilés, Pablo M., Debiec-Rychter, Maria, Sciot, Raf, Schöffski, Patrick
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Neoplasia Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7381700/
https://www.ncbi.nlm.nih.gov/pubmed/32711367
http://dx.doi.org/10.1016/j.tranon.2020.100832
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author Wang, Yannick
Wozniak, Agnieszka
Wellens, Jasmien
Gebreyohannes, Yemarshet K.
Guillén, Maria Jose
Avilés, Pablo M.
Debiec-Rychter, Maria
Sciot, Raf
Schöffski, Patrick
author_facet Wang, Yannick
Wozniak, Agnieszka
Wellens, Jasmien
Gebreyohannes, Yemarshet K.
Guillén, Maria Jose
Avilés, Pablo M.
Debiec-Rychter, Maria
Sciot, Raf
Schöffski, Patrick
author_sort Wang, Yannick
collection PubMed
description The majority of patients with gastrointestinal stromal tumors (GIST) eventually become resistant with time due to secondary mutations in the driver receptor tyrosine kinase. Novel treatments that do not target these receptors may therefore be preferable. For the first time, we evaluated a tubulin inhibitor, plocabulin, in patient-derived xenograft (PDX) models of GIST, a disease generally considered to be resistant to cytotoxic agents. Three PDX models of GIST with different KIT genotype were generated by implanting tumor fragments from patients directly into nude mice. We then used these well characterized models with distinct sensitivity to imatinib to evaluate the efficacy of the novel tubulin inhibitor. The efficacy of the drug was assessed by volumetric analysis of the tumors, histopathology, immunohistochemistry and Western blotting. Plocabulin treatment led to extensive necrosis in all three models and significant tumor shrinkage in two models. This histological response can be explained by the drug's vascular-disruptive properties, which resulted in a shutdown of tumor vasculature, reflected by a decreased total vascular area in the tumor tissue. Our results demonstrated the in vivo efficacy of the novel tubulin inhibitor plocabulin in PDX models of GIST and challenge the established view that GIST are resistant to cytotoxic agents in general and to tubulin inhibitors in particular. Our findings provide a convincing rationale for early clinical exploration of plocabulin in GIST and warrant further exploration of this class of drugs in the management of this common sarcoma subtype.
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spelling pubmed-73817002020-07-28 Plocabulin, a novel tubulin inhibitor, has potent antitumor activity in patient-derived xenograft models of gastrointestinal stromal tumors Wang, Yannick Wozniak, Agnieszka Wellens, Jasmien Gebreyohannes, Yemarshet K. Guillén, Maria Jose Avilés, Pablo M. Debiec-Rychter, Maria Sciot, Raf Schöffski, Patrick Transl Oncol Original article The majority of patients with gastrointestinal stromal tumors (GIST) eventually become resistant with time due to secondary mutations in the driver receptor tyrosine kinase. Novel treatments that do not target these receptors may therefore be preferable. For the first time, we evaluated a tubulin inhibitor, plocabulin, in patient-derived xenograft (PDX) models of GIST, a disease generally considered to be resistant to cytotoxic agents. Three PDX models of GIST with different KIT genotype were generated by implanting tumor fragments from patients directly into nude mice. We then used these well characterized models with distinct sensitivity to imatinib to evaluate the efficacy of the novel tubulin inhibitor. The efficacy of the drug was assessed by volumetric analysis of the tumors, histopathology, immunohistochemistry and Western blotting. Plocabulin treatment led to extensive necrosis in all three models and significant tumor shrinkage in two models. This histological response can be explained by the drug's vascular-disruptive properties, which resulted in a shutdown of tumor vasculature, reflected by a decreased total vascular area in the tumor tissue. Our results demonstrated the in vivo efficacy of the novel tubulin inhibitor plocabulin in PDX models of GIST and challenge the established view that GIST are resistant to cytotoxic agents in general and to tubulin inhibitors in particular. Our findings provide a convincing rationale for early clinical exploration of plocabulin in GIST and warrant further exploration of this class of drugs in the management of this common sarcoma subtype. Neoplasia Press 2020-07-22 /pmc/articles/PMC7381700/ /pubmed/32711367 http://dx.doi.org/10.1016/j.tranon.2020.100832 Text en © 2020 Published by Elsevier Inc. on behalf of Neoplasia Press, Inc. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original article
Wang, Yannick
Wozniak, Agnieszka
Wellens, Jasmien
Gebreyohannes, Yemarshet K.
Guillén, Maria Jose
Avilés, Pablo M.
Debiec-Rychter, Maria
Sciot, Raf
Schöffski, Patrick
Plocabulin, a novel tubulin inhibitor, has potent antitumor activity in patient-derived xenograft models of gastrointestinal stromal tumors
title Plocabulin, a novel tubulin inhibitor, has potent antitumor activity in patient-derived xenograft models of gastrointestinal stromal tumors
title_full Plocabulin, a novel tubulin inhibitor, has potent antitumor activity in patient-derived xenograft models of gastrointestinal stromal tumors
title_fullStr Plocabulin, a novel tubulin inhibitor, has potent antitumor activity in patient-derived xenograft models of gastrointestinal stromal tumors
title_full_unstemmed Plocabulin, a novel tubulin inhibitor, has potent antitumor activity in patient-derived xenograft models of gastrointestinal stromal tumors
title_short Plocabulin, a novel tubulin inhibitor, has potent antitumor activity in patient-derived xenograft models of gastrointestinal stromal tumors
title_sort plocabulin, a novel tubulin inhibitor, has potent antitumor activity in patient-derived xenograft models of gastrointestinal stromal tumors
topic Original article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7381700/
https://www.ncbi.nlm.nih.gov/pubmed/32711367
http://dx.doi.org/10.1016/j.tranon.2020.100832
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