A small-molecule inhibitor of transforming growth factor-β (TGF-β) receptor I kinase could prove to be an effective treatment for human gliomas, according to a recent paper in Cancer Research. The investigational drug, SD-208, was shown to antagonize the immunosuppressive and pro-migratory properties that TGF-β exerts in cancer, and significantly prolonged the median survival of glioma-bearing mice.
Human glioblastoma is an aggressive form of brain cancer for which treatment options are limited and median patient survival is poor. TGF-β has become a key target in the search for more effective drugs because it is one of several immunosuppressive molecules commonly expressed by glioma cells. Although several approaches to inhibit TGF-β are being investigated, such as antisense and gene transfer, the identification of a small molecule that is more amenable to development as an oral drug would be desirable. Martin Uhl and colleagues report such a candidate molecule and describe its antagonistic effect on the biological activity of TGF-β in vitro and in vivo.
TGF-β exerts different biological effects depending on its cellular context and has roles in growth inhibition, immunosuppression and cell migration. The authors first determined whether SD-208 was an effective antagonist of TGF-β in vitro by demonstrating that SD-208 was able to reverse TGF-β-mediated growth inhibition of lung epithelial cells in a concentration-dependent manner. Moreover, SD-208 was able to neutralize the pro-invasive effect of TGF-β observed in assays of cell migratory activity, indicating that SD-208 could possibly prevent the further invasion of gliomas in vivo.
Perhaps most remarkable, however, was the ability of SD-208 to restore an immune response against glioma cells in culture. The lytic activity of peripheral blood lymphocytes or purified T cells was enhanced by co-incubation with SD-208 in a similar way to that observed with TGF-β-neutralizing antibodies, which confirms that the effect occurs through the inhibition of TGF-β. Furthermore, the inhibition of pro-inflammatory cytokine release and natural killer cell activation caused by glioma cells was reversed in the presence of SD-208, whereas release of the immunosuppressive cytokine interleukin-10 was inhibited.
Having established the efficacy of SD-208 in vitro, Uhl and colleagues then went on to study its potential anticancer effect in glioma-bearing mice. Measurement of TGF-β-dependent SMAD2 phosphorylation in mouse brain and spleen confirmed that SD-208 could inhibit TGF-β activity in vivo. Moreover, this inhibition correlated with a delayed onset of neurological symptoms in SD-208-treated glioma-bearing mice compared with untreated controls, and also a significantly improved survival rate after 30 days. These results were reflected by histological analysis, which showed a marked increase in immune infiltration in SD-208-treated mice that had smaller tumours compared with those that had larger tumours, indicating that SD-208 could attenuate the immunosuppression caused by TGF-β in vivo.
The authors conclude that treatment with TGF-β receptor-kinase inhibitors could prove useful to treat gliomas either alone or in combination with existing antisense therapies. Furthermore, SD-208 represents a potential new treatment paradigm in which neutralizing the effect of immunosuppressive cytokines secreted from tumours could be successful as an anticancer strategy.
ORIGINAL RESEARCH PAPER
Uhl, M. et al. SD-208, a novel transforming growth factor β receptor I kinase inhibitor, inhibits growth and invasiveness and enhances immunogenicity of murine and human glioma cells in vitro and in vivo. Cancer Res. 64, 7954–7961 (2004)
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Owens, J. Making gains on glioma. Nat Rev Drug Discov 3, 999 (2004). https://doi.org/10.1038/nrd1599
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DOI: https://doi.org/10.1038/nrd1599