© Copyright 2007 by the Society for Neuro-Oncology
Received March 31, 2006
Accepted November 29, 2006
Basic and Translational Investigations
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Inhibiting TGF-
signaling restores immune surveillance in the SMA-560 glioma model
Thomas-Toan Tran 1,
Martin Uhl 2,
Jing Ying Ma 1,
Lisa Janssen 1,
Venkataraman Sriram 1,
Steffen Aulwurm 2,
Irene Kerr 1,
Andrew Lam 1,
Heather K. Webb 1,
Ann M. Kapoun 1,
Darin E. Kizer 1,
Glenn McEnroe 1,
Barry Hart 1,
Jonathan Axon 1,
Alison Murphy 1,
Sarvajit Chakravarty 1,
Sundeep Dugar 1,
Andrew A. Protter 1,
Linda S. Higgins 1,
Wolfgang Wick 2,
Michael Weller 2,
Darren H. Wong 3*
1 Scios Inc., Fremont, CA, 94555 USA
2 Laboratory of Molecular Neuro-oncology, Department of General Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, School of Medicine, Tübingen, Germany
3 Pfizer RTC, Cambridge, MA 02139, USA
* To whom correspondence should be addressed. E-mail: Darren.H.Wong{at}pfizer.com.
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Abstract |
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Transforming growth factor-
(TGF-) is a proinvasive and immunosuppressive cytokine that plays a major role in the malignant phenotype of gliomas. One novel strategy of disabling TGF- activity in gliomas is to disrupt the signaling cascade at the level of the TGF- receptor I (TGF-RI) kinase, thus abrogating TGF--mediated invasiveness and immune suppression. SX-007, an orally active, small-molecule TGF-RI 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- 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--mediated invasion and reversing immune suppression. SX-007 modulates the TGF- signaling pathway and is associated with improved survival in this glioma model. Survival benefit is due to reduced tumor invasion and reversal of TGF--mediated immune suppression, allowing for rejection of the tumor. Together, these results suggest that treatment with a TGF-RI inhibitor may be useful in the treatment of glioblastoma.
Key Words:
kinases, neuroimmunology, tumor immunity
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