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LY2157299 Monohydrate, a TGF-βR1 Inhibitor, Suppresses Tumor Growth and Ascites Development in Ovarian Cancer.

ABSTRACT: Transforming growth factor beta (TGF-β) signaling has pleiotropic functions regulating cancer initiation, development, and metastasis, and also plays important roles in the interaction between stromal and cancer cells, making the pathway a potential therapeutic target. LY2157299 monohydrate (LY), an inhibitor of TGF-β receptor I (TGFBRI), was examined for its ability to inhibit ovarian cancer (OC) growth both in high-grade serous ovarian cancer (HGSOC) cell lines and xenograft models. Immunohistochemistry, qRT-PCR, and Western blot were performed to study the effect of LY treatment on expression of cancer- and fibroblast-derived genes. Results showed that exposure to TGF-β1 induced phosphorylation of SMAD2 and SMAD3 in all tested OC cell lines, but this induction was suppressed by pretreatment with LY. LY alone inhibited the proliferation, migration, and invasion of HGSOC cells in vitro. TGF-β1-induced fibroblast activation was blocked by LY. LY also delayed tumor growth and suppressed ascites formation in vivo. In addition, independent of tumor inhibition, LY reduces ascites formation in vivo. Using OVCAR8 xenograft specimens we confirmed the inhibitory effect of LY on TGF-β signaling and tumor stromal expression of collagen type XI chain 1 (COL11A1) and versican (VCAN). These observations suggest a role for anti-TGF-β signaling-directed therapy in ovarian cancer.

SUBMITTER: Zhang Q

PROVIDER: S-EPMC6115954 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Anti-tumor activity of the TGF-β receptor kinase inhibitor galunisertib (LY2157299 monohydrate) in patient-derived tumor xenografts.

Project description:PurposeThe transforming growth factor-beta (TGF-β) signaling pathway is known to play a critical role in promoting tumor growth. Consequently, blocking this pathway has been found to inhibit tumor growth. In order to achieve an optimal anti-tumor effect, however, it remains to be established whether blocking the TGF-β signaling pathway alone is sufficient, or whether the tumor microenvironment plays an additional, possibly synergistic, role.MethodsTo investigate the relevance of blocking TGF-β signaling in tumor cells within the context of their respective tissue microenvironments, we treated a panel of patient-derived xenografts (PDX) with the selective TGF-β receptor kinase inhibitor LY2157299 monohydrate (galunisertib) and assessed both the in vitro and in vivo effects.ResultsGalunisertib was found to inhibit the growth in an in vitro clonogenic assay in 6.3% (5/79) of the examined PDX. Evaluation of the expression profiles of a number of genes, representing both canonical and non-canonical TGF-β signaling pathways, revealed that most PDX exhibited expression changes affecting TGF-β downstream signaling. Next, we subjected 13 of the PDX to an in vivo assessment and, by doing so, observed distinct response patterns. These results suggest that, next to intrinsic, also extrinsic or microenvironmental factors can affect galunisertib response. pSMAD2 protein expression and TGF-βRI mRNA expression levels were found to correlate with the in vivo galunisertib effects.ConclusionsFrom our data we conclude that intrinsic, tumor-dependent TGF-β signaling does not fully explain the anti-tumor effect of galunisertib. Hence, in vivo xenograft models may be more appropriate than in vitro clonogenic assays to assess the anti-tumor activity of TGF-β inhibitors such as galunisertib.

| S-EPMC4412926 | biostudies-literature

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