title: Inhibiting TGF-beta 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.
authors.affiliation: Scios Inc., Fremont, CA 94555, USA.
authors.forename: Thomas-Toan
authors.initials: TT
authors.lastname: Tran
authors.forename: Martin
authors.initials: M
authors.lastname: Uhl
authors.forename: Jing Ying
authors.initials: JY
authors.lastname: Ma
authors.forename: Lisa
authors.initials: L
authors.lastname: Janssen
authors.forename: Venkataraman
authors.initials: V
authors.lastname: Sriram
authors.forename: Steffen
authors.initials: S
authors.lastname: Aulwurm
authors.forename: Irene
authors.initials: I
authors.lastname: Kerr
authors.forename: Andrew
authors.initials: A
authors.lastname: Lam
authors.forename: Heather K
authors.initials: HK
authors.lastname: Webb
authors.forename: Ann M
authors.initials: AM
authors.lastname: Kapoun
authors.forename: Darin E
authors.initials: DE
authors.lastname: Kizer
authors.forename: Glenn
authors.initials: G
authors.lastname: McEnroe
authors.forename: Barry
authors.initials: B
authors.lastname: Hart
authors.forename: Jonathan
authors.initials: J
authors.lastname: Axon
authors.forename: Alison
authors.initials: A
authors.lastname: Murphy
authors.forename: Sarvajit
authors.initials: S
authors.lastname: Chakravarty
authors.forename: Sundeep
authors.initials: S
authors.lastname: Dugar
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Protter
authors.forename: Linda S
authors.initials: LS
authors.lastname: Higgins
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wick
authors.forename: Michael
authors.initials: M
authors.lastname: Weller
authors.forename: Darren H
authors.initials: DH
authors.lastname: Wong
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000276:immunology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005910:Glioma / Q000188:drug therapy* / Q000276:immunology; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D007157:Immunologic Surveillance / Q000187:drug effects*; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I