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- W2891037295 abstract "e14055 Background: In preclinical studies eribulin has shown significant effects on epithelial-mesenchymal transition (EMT) in human breast cancer cells in vitro and in vivo, inducing a switch from mesenchymal to epithelial states, decreasing migration and invasiveness of human breast cancer cells in vitro, as well as experimental metastases in vivo. HBI-8000 is a novel, orally bioavailable Class I selective HDAC inhibitor (HDACi). In addition to its demonstrated positive effects on antitumor immunity, it also exerts significant effects on EMT pathway components, enhancing CDH1 (e-cadherin) expression and inhibiting TGF-β induced metastasis. Methods: The syngeneic, orthotopic 4T1 model is thought to be a close representation of the clinical situation; similar to human mammary carcinoma, the major cause of morbidity and mortality is development of spontaneous metastases. 4T1-implanted mice treated with combinations of eribulin and HBI-8000 were monitored for primary tumor growth inhibition (TGI), survival, and metastatic lung foci. Tumor samples were analyzed by Q-PCR for expression of genes involved in EMT or in the metastatic process. Results: Eribulin alone had no effect on primary TGI. Eribulin combined with HBI-8000 resulted in significant (P < 0.05) reductions in median tumor volume, tumor volume distribution (TMD) and survival (P < 0.005). Single agent HBI-8000 had a similar effect on TGI, TMD (P < 0.05) and survival (P < 0.005). Whereas single agent HBI-8000 or eribulin failed to significantly reduce metastases, the eribulin-HBI-8000 combination produced significant (P < 0.01) and synergistic inhibition of metastases, decreasing the number of lung foci approximately 10-fold. Gene expression analyzed by Q-PCR revealed correlations between metastasis blockade and increases in E-Cadherin, Occludin and Claudin1. There was a strong correlation with inhibition of HMGA2 (High Mobility Group AT-Hook 2) gene expression. Conclusions: Eribulin combined with HBI-8000 inhibited primary tumor growth and inhibited metastasis development and increased survival. This effect was correlated and consistent with changes in genes relevant to EMT, tumor plasticity and stemness." @default.
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- W2891037295 date "2017-05-20" @default.
- W2891037295 modified "2023-09-25" @default.
- W2891037295 title "The activity of the HDAC inhibitor HBI-8000 (Chidamide) combined with eribulin on 4T1 spontaneous metastasis development." @default.
- W2891037295 doi "https://doi.org/10.1200/jco.2017.35.15_suppl.e14055" @default.
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