A Novel Small-Molecule Inhibitor of Transforming Growth Factor {szligbeta} Type I Receptor Kinase (SM16) Inhibits Murine Mesothelioma Tumor Growth In vivo and Prevents Tumor Recurrence after Surgical Resection

Malignant mesothelioma is an aggressive and lethal pleural cancer that overexpresses transforming growth factor {szligbeta} (TGF{szligbeta}). We investigated the efficacy of a novel small-molecule TGF{szligbeta} type I receptor (ALK5) kinase inhibitor, SM16, in the AB12 syngeneic model of malignant mesothelioma. SM16 inhibited TGF{szligbeta} signaling seen as decreased phosphorylated Smad2/3 levels in cultured AB12 cells (IC sub(50), similar to 200 nmol/L). SM16 penetrated tumor cells in vivo, suppressing tumor phosphorylated Smad2/3 levels for at least 3 h following treatment of tumor-bearing mice with a single i.p. bolus of 20 mg/kg SM16. The growth of established AB12 tumors was significantly inhibited by 5 mg/kg/d SM16 (P < 0.001) delivered via s.c. miniosmotic pumps over 28 days. The efficacy of SM16 was a result of a CD8 super(+) antitumor response because (a) the antitumor effects were markedly diminished in severe combined immunodeficient mice and (b) CD8 super(+) T cells isolated from spleens of mice treated with SM16 showed strong antitumor cytolytic effects whereas CD8 super(+) T cells isolated from spleens of tumor-bearing mice treated with control vehicle showed minimal activity. Treatment of mice bearing large tumors with 5 mg/kg/d SM16 after debulking surgery reduced the extent of tumor recurrence from 80% to