In:
Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 34, No. 4_suppl ( 2016-02-01), p. 50-50
Abstract:
50 Background: TGF-β signaling is known to promote epithelial-mesenchymal transition (EMT) of tumor cells, thus producing tumor progression, invasion, and metastasis. Therefore, this signaling has been expected to be a new target of cancer therapy. In this study, we evaluated the antitumor effect of LY2157299, a TGF-βR1 kinase inhibitor, alone and in combination with 5-fluorouracil (5-FU) or paclitaxel (PTX), key agents in the treatment of gastric cancer (GC). Methods: TGF-β inhibition impedes phosphorylation of Smad2 and induces the expression of vimentin, an EMT marker. Vimentin expression was examined +/- LY2157299 by western blot. The phenotypic change of human GC cell, 44As3-Luc after TGF-β and LY2157299 treatment was assessed by Matrigel migration/invasion assay. The in vitro cytocidal effect and in vivo antitumor effect of LY2157299 alone or with either 5-FU or PTX were evaluated by water soluble tetrazolium-1 (WST-1) assay and by xenograft mouse model, respectively. Results: The phosphorylation of Smad2, the expression of vimentin and the optical mesenchymal transformation in 44As3-Luc induced by TGF-β were successfully suppressed by LY2157299. Accordingly, the activity of migration and invasion evoked by TGF-β was suppressed significantly by co-administration of LY2157299 with TGF-β. Although LY2157299 monotherapy did not show a tumor suppressive effect and LY2157299 did not potentiate the cell toxicity of 5-FU and PTX in vitro, LY2157299 reduced tumor volume (TV) of 44As3-Luc xenografts by 64% of control (p 〈 0.05). 5-FU + LY2157299 treatment reduced TV of 5-FU alone by 52% (p 〈 0.05) and PTX + LY2157299 treatment also reduced TV of PTX alone by 52% (p 〈 0.05). These results suggest that LY2157299 suppresses tumor growth possibly through some effect of LY2157299 in tumor-stroma environment. Conclusions: LY2157299 inhibited migration and invasion of GC cell line. Moreover, the monotherapy of LY2157299 and the combination therapy of LY2157299 with 5-FU or PTX significantly suppressed tumor growth. These findings warrant clinical evaluation of LY2157299 in patients with GC.
Type of Medium:
Online Resource
ISSN:
0732-183X
,
1527-7755
DOI:
10.1200/jco.2016.34.4_suppl.50
Language:
English
Publisher:
American Society of Clinical Oncology (ASCO)
Publication Date:
2016
detail.hit.zdb_id:
2005181-5
