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

Qing Zhang,Bradley Evans,Saravut Weroha,William Cliby,Xiaonan Hou,Jamison Vanblaricom

doi:10.3390/cancers10080260

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.

Highlights

Ovarian cancer (OC) is the most lethal gynecologic cancer, with an estimated 238,700 new cases annually worldwide [1]
Real-time Quantitative PCR (qPCR) was performed to evaluate the mRNA expression of two TGF-β signaling pathway-related genes, TGFBI and TGFBRI, across eight ovarian cancer (OC) cell lines
We confirmed that all tested cell lines are capable of inducing phosphorylation of SMAD2 (p-SMAD2) and phosphorylation of SMAD3 (p-SMAD3) in response to TGF-β1 stimulation (Figure 1C), suggesting intact TGF-β signaling

Summary

Introduction

Ovarian cancer (OC) is the most lethal gynecologic cancer, with an estimated 238,700 new cases annually worldwide [1]. In the United States alone there will be an estimated 14,070 deaths during. The standard treatment for OC is primary surgical cytoreduction followed by adjuvant chemotherapy. 70% of the patients respond well to the initial adjuvant chemotherapy, most of these patients relapse and evolve to a chemoresistant phenotype. Attempts to delay the onset of recurrence or chemoresistance following first-line therapy by use of maintenance therapy have only shown modest improvements [3,4,5,6,7,8]. In OC, cancer-associated stroma stimulates proliferation, migration, and invasion and these effects are at least partially modulated by transforming growth factor beta (TGF-β) signaling [9,10]

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Discussion

Conclusion