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.
journal_name
Neuro Oncoljournal_title
Neuro-oncologyauthors
Tran TT,Uhl M,Ma JY,Janssen L,Sriram V,Aulwurm S,Kerr I,Lam A,Webb HK,Kapoun AM,Kizer DE,McEnroe G,Hart B,Axon J,Murphy A,Chakravarty S,Dugar S,Protter AA,Higgins LS,Wick W,Weller M,Wong DHdoi
10.1215/15228517-2007-010subject
Has Abstractpub_date
2007-07-01 00:00:00pages
259-70issue
3eissn
1522-8517issn
1523-5866pii
15228517-2007-010journal_volume
9pub_type
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