Plocabulin, a novel tubulin inhibitor, has potent antitumor activity in patient-derived xenograft models of gastrointestinal stromal tumors.
Gastrointestinal stromal tumor
PM060184
Patient-derived xenograft
Plocabulin
Tubulin inhibitor
Journal
Translational oncology
ISSN: 1936-5233
Titre abrégé: Transl Oncol
Pays: United States
ID NLM: 101472619
Informations de publication
Date de publication:
Nov 2020
Nov 2020
Historique:
received:
14
04
2020
accepted:
16
06
2020
pubmed:
28
7
2020
medline:
28
7
2020
entrez:
26
7
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32711367
pii: S1936-5233(20)30324-7
doi: 10.1016/j.tranon.2020.100832
pmc: PMC7381700
pii:
doi:
Types de publication
Journal Article
Langues
eng
Pagination
100832Informations de copyright
Copyright © 2020. Published by Elsevier Inc.
Déclaration de conflit d'intérêts
Declaration of competing interest Yannick Wang received travel support from PharmaMar. Maria Jose Guillén and Pablo M. Avilés are employees of PharmaMar. Patrick Schöffski received institutional support from PharmaMar for research funding. Other authors declare no potential conflicts of interest.
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