Oliver Schadt

Abstract 925: The c-Met inhibitor MSC2156119J effectively inhibits growth of liver cancer models.

The mesenchymal-epithelial transition factor (c-Met) receptor, also known as hepatocyte growth factor receptor (HGFR), controls morphogenesis, a process physiologically required for embryonic development and tissue repair. Aberrant c-Met activation is associated with human malignancies, including hepatocellular carcinomas (HCC). The aim of this study was to evaluate the effect of a novel, highly selective c-Met inhibitor, MSC2156119J (EMD 1214063), in hepatocellular cancer models. MHCC97H is a human HCC cell line co-expressing c-Met and HGF, and exhibiting high metastatic potential. The effect of MSC2156119J on MHCC97H was evaluated in a Balb/c nu/nu murine xenograft model in a subcutaneous and orthotopic setting. Tumor-bearing mice were orally treated with 100 mg/kg MSC2156119J (5 days on/2 days off). In the subcutaneous setting, MSC2156119J resulted in tumor regression in 10/10 mice, achieving tumor eradication in 9/10 mice. In the orthotopic model, MHCC97H tumor fragments proliferate in the liver and invariably metastasize to the lung (100%). MSC2156119J treatment started 7 days after tumor fragment implantation. After 5 weeks of treatment, mice were necropsied and a series of parameters were assessed. Primary tumor size and weight, and circulating Alpha-Feto-Protein levels were significantly lower in mice treated with MSC2156119J compared to controls (p To better predict the clinical efficacy of MSC2156119J, 9 patient-derived primary HCC explants models were used. The explants were subdivided into 3 groups, based on their c-Met levels and HGF expression. Each group comprised 3 tumors expressing high, intermediate, and low levels of c-Met and HGF, respectively. Mice were treated with MSC2156119J, sorafenib, or a combination of both. MSC2156119J (100 mg/kg/5 out of 7 days) strongly inhibited tumor growth in 4/9 models (TGD range of 370% to 41%). Analysis of intratumoral c-Met, phospho c-Met and HGF levels indicated that explants with high levels of c-Met and HGF were more sensitive to MSC2156119J than low-expressing models. In 3/4 responsive models, MSC2156119J exhibited a better anti-tumor activity than sorafenib, while sorafenib was more efficacious in a model characterized by intermediate c-Met/HGF expression. MSC2156119J was not efficacious in models exhibiting low or no signs of c-Met signalling. When used in combination, MSC2156119J did not enhance the activity of sorafenib. MSC2156119J monotherapy was well tolerated while sorafenib alone and in combination with MSC2156119J induced significant body weight loss. Overall, these data indicate that MSC2156119J may be a valuable therapeutic option for liver cancers with high levels of c-Met expression/activation. Citation Format: Friedhelm Bladt, Andree Blaukat, Dieter Dorsch, Manja Friese-Hamim, Michael Meyring, Oliver Schadt. The c-Met inhibitor MSC2156119J effectively inhibits growth of liver cancer models. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 925. doi:10.1158/1538-7445.AM2013-925