Effect of the combination of mTOR inhibitor ridaforolimus and HDAC inhibitor vorinostat on in vitro synergism in synovial sarcoma, osteosarcoma, and a range of other tumor subtypes.

Abstract

10080 Background: Curative treatments for patients with metastatic synovial sarcoma (SS) do not exist, and such patients have a poor prognosis. We explored combinations of molecularly-targeted and cytotoxic agents to identify synergistic treatment combinations in SS cells. Methods: Two SS cell lines (HS-SY-II and SYO-I) were treated with single agents or combinations of molecularly targeted therapies (HDAC inhibitor, vorinostat; mTOR inhibitor, ridaforolimus) and cytotoxic agents. After 72 hours, cell viability was measured using the cell proliferation assay (MTS). Combination Indices (CI) were calculated to determine whether each combination was synergistic, additive, or antagonistic. The most active combination was selected for further confirmation in other tumor subtypes. Results: Ridaforolimus IC50 was 10.9nM in HS-SY-II and 23.1nM in SYO-I, vorinostat IC50 was 440nM in HS-SY-II and 561nM in SYO-I, doxorubicin IC50 was 9.4nM in HS-SY-II and 7.4nM in SYO-I, and melphalan IC50 was 687nM in HS-SY-II and 859nM in SYO-I. Synergism was observed in cells treated with ridaforolimus/vorinostat: CI was 0.28 and 0.63 in HS-SY-II and SYO-I, respectively. Both ridaforolimus/doxorubicin and ridaforolimus/melphalan exhibited synergism: CI ranged from 0.50 to 0.59 in HS-SY-II and SYO-I. Additive effects were observed when vorinostat was combined with doxorubicin or melphalan. Given its strong synergism, the ridaforolimus/vorinostat combination was assessed in osteosarcoma (U2OS), metastatic melanoma (Stew1 and Stew2), pancreatic cancer (Panc1 and BxPC3), and lung cancer (A549). The combination was synergistic in all cell lines: CI ranged from 0.37 to 0.77, except in Panc1, where it was additive (CI of 0.92). Conclusions: The combination of ridaforolimus and vorinostat is synergistic in vitro in SS as well as in a variety of tumor types, including osteosarcoma, melanoma, pancreatic cancer, non-small cell lung cancer. In anticipation of human studies, further in vitro studies are planned to assess the activity of this combination in other sarcomas subtypes and in vivo. Studies to assess the molecular basis for this synergism are also planned.