Abstract C265: Significant in vivo activity of ENMD-2076, a novel multi-targeted kinase inhibitor, towards xenograft models of human hepatocellular carcinomas .

Abstract

Abstract Background: Hepatocellular carcinoma (HCC) is a primary malignancy of the liver. It represents the third leading cause of cancer deaths worldwide, with over 500,000 people affected each year. The incidence of HCC is particularly high in China, accounting for more than 50% of the global incidences. The development of targeted anticancer agents effective against HCC for patients who do not tolerate, or have failed or relapsed from sorafenib treatment would meet a major unmet medical need. ENMD-2076 is an orally bioavailable small molecule inhibitor of Aurora A and angiogenic kinases including VEGFR 2 and FGFR 1 with pro-apoptotic, antiproliferative and angiogenic activities against a variety of human cancers. ENMD-2076 has been tested in multiple Phase I and II clinical trials, with partial responses (PR) and prolonged progression free survival (PFS) observed in multiple cancers including liver cancer. Objective: This in vivo study was designed to compare the efficacy of ENMD-2076 with that of standard of care agents including sorafenib, doxorubicin, and 5-FU in 3 different cell-line derived human HCC xenograft models. The tolerability and efficacy of combinations of ENMD-2076 with doxorubicin or 5-FU were also determined. Experimental Design: Three different human HCC cell lines, SMMC-7721, QGY-7703 and HepG 2 were used for establishing subcutaneous tumor xenograft models in nude mice. After tumors grew to more than 100 mm3, mice were randomly assigned into one of the groups receiving vehicle, sorafenib, ENMD-2076 alone or in combination with chemotherapy agents, including doxorubicin or 5-FU, respectively, for 20 days. Results: In all HCC models tested, ENMD-2076 induced tumor growth inhibition significantly greater than that of sorafenib. When treated with ENMD-2076 at 100 mg/kg, the tumor growth inhibition (TGI) rates were 73.67%, 76.59% or 80.12% in the SMMC-7721, QGY-7703 or HepG 2 models, respectively, which were significantly higher than those observed in sorafenib treated groups (48.63%, 51.43%, or 57.60%, respectively;P<0.01 in all three models). Tumor growth inhibition rates were similarly higher in the ENMD-2076 treated groups than in groups treated with doxorubicin at 1 mg/kg and 5-FU at 30 mg/kg. The combined treatment of ENMD-2076 with either doxorubicin or 5-FU was well tolerated. Higher TGI rates were observed in combination groups compared to single agents of chemotherapies but were not statistically different. Conclusion: ENMD-2076 showed robust antitumor activity against three cell line-derived xenograft models of HCC superior to that of sorafenib, doxorubicin, and 5FU, supporting clinical investigation of this agent in HCC patients who do not tolerate, or have failed or relapsed from other systemic treatment such as sorafenib, doxorubicin or 5 FU. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C265. Citation Format: Peipei Yin, Hongqi Lu, Mark R. Bray, Bingsheng Li, Ken Ren. Significant in vivo activity of ENMD-2076, a novel multi-targeted kinase inhibitor, towards xenograft models of human hepatocellular carcinomas . [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C265.