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[Cancer Research 64, 7954-7961, November 1, 2004]
© 2004 American Association for Cancer Research

Regular Articles

SD-208, a Novel Transforming Growth Factor ß Receptor I Kinase Inhibitor, Inhibits Growth and Invasiveness and Enhances Immunogenicity of Murine and Human Glioma Cells In vitro and In vivo

Martin Uhl1, Steffen Aulwurm1, Jörg Wischhusen1, Markus Weiler1, Jing Ying Ma2, Ramona Almirez2, Ruban Mangadu2, Yu-Wang Liu2, Michael Platten1, Ulrich Herrlinger1, Alison Murphy2, Darren H. Wong2, Wolfgang Wick1, Linda S. Higgins2 and Michael Weller1

1 Laboratory of Molecular Neuro-Oncology, Department of General Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, School of Medicine, Tübingen, Germany; and 2 Scios Inc., Fremont, California

The cytokine transforming growth factor (TGF)-ß, by virtue of its immunosuppressive and promigratory properties, has become a major target for the experimental treatment of human malignant gliomas. Here we characterize the effects of a novel TGF-ß receptor (TGF-ßR) I kinase inhibitor, SD-208, on the growth and immunogenicity of murine SMA-560 and human LN-308 glioma cells in vitro and the growth of and immune response to intracranial SMA-560 gliomas in syngeneic VM/Dk mice in vivo. SD-208 inhibits the growth inhibition of TGF-ß–sensitive CCL64 cells mediated by recombinant TGF-ß1 or TGF-ß2 or of TGF-ß–containing glioma cell supernatant at an EC50 of 0.1 µmol/L. SD-208 blocks autocrine and paracrine TGF-ß signaling in glioma cells as detected by the phosphorylation of Smad2 or TGF-ß reporter assays and strongly inhibits constitutive and TGF-ß–evoked migration and invasion, but not viability or proliferation. Peripheral blood lymphocytes or purified T cells, cocultured with TGF-ß–releasing LN-308 glioma cells in the presence of SD-208, exhibit enhanced lytic activity against LN-308 targets. The release of interferon {gamma} and tumor necrosis factor {alpha} by these immune effector cells is enhanced by SD-208, whereas the release of interleukin 10 is reduced. SD-208 restores the lytic activity of polyclonal natural killer cells against glioma cells in the presence of recombinant TGF-ß or of TGF-ß–containing glioma cell supernatant. The oral bioavailability of SD-208 was verified by demonstrating the inhibition of TGF-ß–induced Smad phosphorylation in spleen and brain. Systemic SD-208 treatment initiated 3 days after the implantation of SMA-560 cells into the brains of syngeneic VM/Dk mice prolongs their median survival from 18.6 to 25.1 days. Histologic analysis revealed no difference in blood vessel formation, proliferation, or apoptosis. However, animals responding to SD-208 showed an increased tumor infiltration by natural killer cells, CD8 T cells, and macrophages. These data define TGF-ß receptor I kinase inhibitors such as SD-208 as promising novel agents for the treatment of human malignant glioma and other conditions associated with pathological TGF-ß activity.




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