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

Abstract

Malignant mesothelioma is an aggressive and lethal pleural cancer that overexpresses transforming growth factor B (TGFB). We investigated the efficacy of a novel small-molecule TGFB type I receptor (ALK5) kinase inhibitor, SM16, in the AB12 syngeneic model of malignant mesothelioma. SM16 inhibited TGFB signaling seen as decreased phosphorylated Smad2/3 levels in cultured AB12 cells (IC 50 , f200 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 + antitumor response because (a) the antitumor effects were markedly diminished in severe combined immunodeficient mice and (b) CD8 + T cells isolated from spleens of mice treated with SM16 showed strong antitumor cytolytic effects whereas CD8 + 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 <20% (P < 0.05). SM16 was also highly effective in blocking and regressing tumors when given p.o. at doses of 0.45 or 0.65 g/kg in mouse chow. Thus, SM16 shows potent activity against established AB12 malignant mesothelioma tumors using an immune-mediated mechanism and can significantly prevent tumor recurrence after resection of bulky AB12 malignant mesothelioma tumors. These data suggest that ALK5 inhibitors, such as SM16, offer significant potential for the treatment of malignant mesothelioma and possibly other cancers.

Retraction: GQ5 Hinders Renal Fibrosis in Obstructive Nephropathy by Selectively Inhibiting TGF-β–Induced Smad3 Phosphorylation

“…Molecules that inhibit TGF-b binding to its receptor are being developed including decorin, 37 soluble chimeric TGF-b receptor, 38,39 neutralizing antibodies against TGF-b, 40,41 and small molecule inhibitors for TbRI activin receptor-like kinase 5. 29,[42][43][44] In this study, we found that GQ5 markedly inhibited TGF-b1-induced Smad3 phosphorylation, whereas such an effect was almost undetectable in the absence of TGF-b1 stimulation. Given that upregulation of TGF-b1 and overt Smad3 phosphorylation are present only in diseased states, GQ5 might play a therapeutic role in fibrotic tissue without interfering the constitutional activity of TGF-b1 signaling.…”

Changes in the local tumor microenvironment in recurrent cancers may explain the failure of vaccines after surgery

“…Small-molecule inhibitors of TGF-β type I receptor (ALK5) kinase have been previously described (31). SM16 (Oncology Cell Signaling, Biogen Idec, Cambridge, MA) is an ALK5/ALK4 kinase inhibitor with a molecular weight of 430.…”

Signaling Receptors for TGF-β Family Members

“…These compounds often compete with binding of ATP to the ATP-binding site of the kinase, and several of them inhibit the TbRI kinase selectively, but often also inhibit the activin type I receptor ALK-4 and the nodal type I receptor ALK-7 (Yingling et al 2004). TbRI kinase inhibitors have been shown, in animal models, to inhibit invasion and metastasis of, for example, breast cancer cells (Bandyopadhyay et al 2006;Ge et al 2006;Ehata et al 2007;Liu et al 2012), melanoma cells (Mohammad et al 2011), glioma cells (Uhl et al 2004;Zhang et al 2011), and mesothelioma cells (Suzuki et al 2007). The effect of the inhibitors include inhibition of mesenchymal transition of the tumor cells, activation of the immune system, inhibition of angiogenesis, inhibition of osteolysis preventing bone metastasis, and normalization of tumor stroma.…”