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

Abstract

Transforming growth factor-β (TGF-β) is a preinvasive and immunosuppressive cytokine that plays a major role in the malignant phenotype of gliomas. One novel strategy of disabling TGF-β activity in gliomas is to disrupt the signaling cascade at the level of the TGF-β receptor I (TGF-βRI) kinase, thus abrogating TGF-β-mediated invasiveness and immune suppression. SX-007, an orally active, small-molecule TGF-βRI 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-β 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-β-mediated invasion and reversing immune suppression. SX-007 modulates the TGF-β signaling pathway and is associated with improved survival in this glioma model. Survival benefit is due to reduced tumor invasion and reversal of TGF-β-mediated immune suppression, allowing for rejection of the tumor. Together, these results suggest that treatment with a TGF-βRI inhibitor may be useful in the treatment of glioblastoma. Copyright 2007 by the Society for Neuro-Oncology.