Inhibiting TGF-β signaling restores immune surveillance in the SMA-560 glioma model

Abstract

Transforming growth factor-beta (TGF-beta) is a proinvasive and immunosuppressive cytokine that plays a major role in the malignant phenotype of gliomas. One novel strategy of disabling TGF-beta activity in gliomas is to disrupt the signaling cascade at the level of the TGF-beta receptor I (TGF-betaRI) kinase, thus abrogating TGF-beta-mediated invasiveness and immune suppression. SX-007, an orally active, small-molecule TGF-betaRI kinase inhibitor, was evaluated for its therapeutic potential in cell culture and in an in vivo glioma model. The syngeneic, orthotopic glioma model SMA-560 was used to evaluate the efficacy of SX-007. Cells were implanted into the striatum of VM/Dk mice. Dosing began three days after implantation and continued until the end of the study. Efficacy was established by assessing survival benefit. SX-007 dosed at 20 mg/kg p.o. once daily (q.d.) modulated TGF-beta signaling in the tumor and improved the median survival. Strikingly, approximately 25% of the treated animals were disease-free at the end of the study. Increasing the dose to 40 mg/kg q.d. or 20 mg/kg twice daily did not further improve efficacy. The data suggest that SX-007 can exert a therapeutic effect by reducing TGF-beta-mediated invasion and reversing immune suppression. SX-007 modulates the TGF-beta signaling pathway and is associated with improved survival in this glioma model. Survival benefit is due to reduced tumor invasion and reversal of TGF-beta-mediated immune suppression, allowing for rejection of the tumor. Together, these results suggest that treatment with a TGF-betaRI inhibitor may be useful in the treatment of glioblastoma.

Effector T-Cell Infiltration Positively Impacts Survival of Glioblastoma Patients and Is Impaired by Tumor-Derived TGF-β

“…Thus, blocking TGF-b signaling would seem to be a useful strategy in glioma treatment. In animal models of glioma, treatment with the TGF-b receptor small molecule inhibitor, SD-208, caused increased animal survival and increased immune cell infiltration (35,49). Consistent with these results, we found that treating glioma-derived endothelial cells with SD-208 significantly enhanced the transmigration of autologous T cells.…”

Targeting the transforming growth factor-β signaling pathway in human cancer

“…Recent study with administration of the TGFβRI kinase inhibitor SD-208 to mice bearing intracranial SMA-560 gliomas resulted in increased infiltration of the tumor with immune effector cells and prolonged survival (86). Similar results in the SMA-560 model have been obtained using SX-007, an orally bioavailable pyridopyrimidine TGFβRI kinase inhibitor (87). Indeed, SB-431542, SB-505124, and LY580276 also inhibit activin receptor-like kinases ALK-4 and ALK-7 besides TGFβRI (ALK-5), which indicates that they can inhibit activin-mediated activation of Smad2 and Smad3 (82, 88).…”

Tissue invasion and metastasis: Molecular, biological and clinical perspectives

“…The combination of SM16 with anti-OX40 elicited a potent antitumor effect against established poorly immunogenic, highly metastatic, TGF-␤-secreting primary 4T1 mammary tumors, with a 79% reduction in tumor size, a 95% reduction in the number of metastatic lung nodules, and a cure rate of 38% [266]. SX-007, an orally active, pyridopyrimidine ALK5 kinase inhibitor, was also evaluated for its therapeutic potential in cell culture and in the syngeneic, orthotopic glioma model SMA-560, where it exerted a therapeutic effect by reducing TGF-␤-mediated invasion, reversing immune suppression and improving survival in this model [267]. The IN-1130 inhibitor has also displayed antitumor effects in mice injected subcutaneously with the murine prostate cancer cell line Tramp C2.…”