TY - JOUR T1 - An Orally Active Small Molecule TGF-β Receptor I Antagonist Inhibits the Growth of Metastatic Murine Breast Cancer JF - Anticancer Research JO - Anticancer Res SP - 2099 LP - 2109 VL - 29 IS - 6 AU - MATTHEW P. RAUSCH AU - TOBIAS HAHN AU - LALITHA RAMANATHAPURAM AU - DEBORAH BRADLEY-DUNLOP AU - DARUKA MAHADEVAN AU - MELANIA E. MERCADO-PIMENTEL AU - RAYMOND B. RUNYAN AU - DAVID G. BESSELSEN AU - XIAMEI ZHANG AU - H.-KAM CHEUNG AU - WEN-CHERNG LEE AU - LEONA E. LING AU - EMMANUEL T. AKPORIAYE Y1 - 2009/06/01 UR - http://ar.iiarjournals.org/content/29/6/2099.abstract N2 - Background: Transforming growth factor β (TGF-β) plays a complex role in breast carcinogenesis. Initially functioning as a tumor suppressor, this cytokine later contributes to the progression of malignant cells by enhancing their invasive and metastatic potential as well as suppressing antitumor immunity. The purpose of this study was to investigate the efficacy of SM16, a novel small molecule ALK5 kinase inhibitor, to treat a highly metastatic, TGF-β-producing murine mammary carcinoma (4T1). Materials and Methods: Mice bearing established 4T1 tumors were treated with SM16 intraperitoneally (i.p.) or orally, and primary and metastatic tumor growth was assessed. Results: SM16 inhibited Smad2 phosphorylation in cultured 4T1 tumor cells as well as primary and metastatic 4T1 tumor tissue. Blockade of TGF-β signal transduction in 4T1 tumor cells by SM16 prevented TGF-β-induced morphological changes and inhibited TGF-β-induced invasion in vitro. When delivered via daily i.p. injection or orally through mouse chow, SM16 inhibited the growth of primary and metastatic 4T1 tumors. Splenocytes isolated from mice on the SM16 diet displayed enhanced IFN-γ production and antitumor CTL activity. Furthermore, SM16 failed to inhibit the growth and metastasis of established 4T1 tumors in immunodeficient SCID mice. Conclusion: Taken together, the data indicate that the antitumor efficacy of SM16 is dependent on an immune-mediated mechanism and that SM16 may represent a safe and effective treatment for metastatic breast cancer. ER -