Abstract 5436: The histone deacetylase inhibitor SB939 acts synergistically with Sorafenib in an orthotopic model of hepatucellular carcinoma

Abstract

Abstract Introduction: SB939 is an hydroxamic acid based class I, II and IV HDAC inhibitor, with very favourable physiochemical, pharmaceutical and pharmacokinetic properties, resulting in an excellent bioavailability and marked accumulation in tumor tissue. In clinical phase I studies with SB939 in solid tumors, drug exposure was demonstrated to be higher and side effects milder/fewer compared to first generation HDAC inhibitors such as SAHA. Only 6.7% Grade3/4 fatigue (2/30 patients) or 6.9% (2/29 patients) were observed in two independent Phase I clinical studies making SB939 ideally suited for combination therapies. The aim of the present studies was to explore the potential of SB939 for the treatment of hepatocellular carcinoma (HCC). Methods: The effects of SB939 as single agent and combination therapy on the proliferation of HCC cell lines were explored in vitro studies. Single agent and combination therapy together with Sorafenib (Nexavar), a multitargeted VEGFR-b-Raf kinase inhibitor, which is now standard therapy for HCC, was explored in an orthotopic xenograft model of HCC, using Hep3B cells in female SCID mice. Mice were dosed daily with either 10 or 45 mg/kg Sorafenib per oral (p.o.) or with 125 mg/kg SB939 p.o. every other day, alone or in combination with Sorafenib. Sorafenib was dosed first and SB939 dosed 6 h thereafter. Plasma and tumor concentrations of SB939 and Sorafenib were measured using HPLC/MS, analyzed with the MassLynx software and PK parameters were calculated by a non-compartmental method using WinNonlin 4.0 software. Pharmacodynamic (PD) parameters such as HDAC inhibition, inhibition of the Raf-ras MAPK pathway, as well as anti-angiogenic effects of the treatment were analyzed by Western blotting and immunohistochemistry of tumor tissue. Results: HCC cell lines did not show high sensitivity to the anti-proliferative effects of either Sorafanib or SB939 (IC50 values for SB939 ranging from 0.9 to 1.23 μM). In contrast, in the in vivo model of HCC, Sorafenib at a dose of 10 mg/kg had no significant effect on tumor growth (tumor growth inhibition [TGI] was −12.6%), but a dose of 45 mg/kg was very effective (82% TGI). SB939 at a maximum tolerated dose and schedule was well tolerated and moderately effective in arresting tumor grow (40% TGI). When combined with the ineffective lower dose of Sorafenib, the anti-tumor efficacy of SB939 was significantly enhanced (58% TGI), with an in vivo combinatorial index of 0.4, indicating synergy. Conclusion: Although the Hep3B cell line is quite resistant to SB939 in vitro, SB939 is moderately effective as single agent therapy. Anti-tumor efficacy of SB939 was synergistically enhanced in combination with a low and ineffective dose of the VEGFR-Raf tyrosine kinase inhibitor Sorafenib, and the combination was well tolerated, providing a rationale for a phase II trial in combination with Sorafenib in HCC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5436.