Hsp90 and histone deactylase inhibitor have synergistic activity against synovial sarcoma.

B50

Clinically-applicable Hsp90 and histone deacetylase inhibitors have independently been shown to suppress growth and induce apoptosis in synovial sarcoma; this study tests the hypothesis that such agents may be synergistic, which would permit increased efficacy while reducing dose and minimizing potential side effects. Synovial sarcoma is an aggressive soft tissue malignancy of unknown cellular origin, which typically affects young adults and often proves fatal. The chromosomal translocation t(X;18)(p11.2;q11.2) resulting in the fusion oncoprotein SYT-SSX is characteristic of this disease, but its function in oncogenesis is unclear. Synovial sarcoma exhibits an undifferentiated mesenchymal phenotype that suggests its malignant transformation involves dysfunctional cellular differentiation. The Hsp90 inhibitor 17AAG is being tested in clinical trials in a variety of cancers including leukemias, lymphomas, and sarcomas. Histone deacetylase inhibitors (including MS-275) are also currently involved in clinical trials of several cancers including leukemias and lymphomas and are considered to be promising new therapies for a wide range of cancers. Recently, we (Terry J et al. Clin Cancer Res 2005;11:5641) and others (Ito T et al. Cancer Lett 2005;224:311) have found that both 17AAG and histone deacetylase inhibitors, as single agents, are successful in arresting growth of synovial sarcoma in vitro and slowing growth in xenografts. We therefore tested combinations of 17AAG with the histone deacetylase inhibitor MS-275 by MTT proliferation assays and by Annexin V flow cytometry apoptosis assay, using established synovial sarcoma cell line models. Synergism was assessed by the median-effect principle of Chou and Talalay. As single agents, the IC50 for 17AAG is 2.1 uM and for MS275 is 4.5 uM at 24 hours in these assays. In synovial sarcoma cell line SYO-1, 50% reduction in MTT absorbance at 24 hours was achieved by a combination of 0.1 uM 17AAG with 0.25 uM MS-275. This result is nine times more effective than if the drugs were simply additive. Synergistic effects were still present at later assay time points, and in the synovial sarcoma cell line Fuji. These results show, for the first time, that 17AAG and histone deacetylase inhibitors are synergistic against synovial sarcoma in vitro and suggest that low dose combination therapies may be effective against this disease.