|
|
|
|
|
|
||
|
|
||||
|
|
||||
|
||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Basic and Translational Investigations |
Scios Inc., Fremont, CA 94555 USA (T.-T.T., J.Y.M., L.J., V.S., I.K., A.L., H.K.W., A.M.K., D.E.K., G.M., B.H., J.A., A.M., S.C., S.D., A.A.P., L.S.H.); Laboratory of Molecular Neuro-oncology, Department of General Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, School of Medicine, Tübingen, Germany (M.U., S.A., W.W., M.W.); Pfizer RTC, Cambridge, MA 02139, USA (D.H.W.)
Address correspondence to Darren H. Wong, Pfizer RTC, 620 Memorial Drive, Cambridge, MA 02139, USA (Darren.H.Wong{at}pfizer.com).
Transforming growth factor-ß (TGF-ß) is a proinvasive and immunosuppressive cytokine that plays a major role in the malignant phenotype of gliomas. One novel strategy of disabling TGF-ß activity in gliomas is to disrupt the signaling cascade at the level of the TGF-ß receptor I (TGF-ßRI) kinase, thus abrogating TGF-ß-mediated invasiveness and immune suppression. SX-007, an orally active, small-molecule TGF-ßRI 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-ß 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-ß-mediated invasion and reversing immune suppression. SX-007 modulates the TGF-ß signaling pathway and is associated with improved survival in this glioma model. Survival benefit is due to reduced tumor invasion and reversal of TGF-ß-mediated immune suppression, allowing for rejection of the tumor. Together, these results suggest that treatment with a TGF-ßRI inhibitor may be useful in the treatment of glioblastoma.
Key Words: kinases • neuroimmunology • tumor immunity
|
|
