INTRODUCTION: INC280 is an oral, highly selective c-Met receptor tyrosine kinase inhibitor. The hepatocyte growth factor (HGF)-c-Met pathway is one of the most frequently dysregulated pathways in human cancers. Aberrant HGF-c-Met signaling has been documented in a wide range of human malignancies. The c-Met pathway can be activated by abnormal HGF and c-Met expression levels, c-Met activating mutations and gene amplifications. At this time, INC280 is in development for the treatment of solid tumors with activation of the c-Met pathway. As a part of this study, we looked at the antitumoral activity of INC280 in adult glioblastoma (GBM) brain tumor xenografts with elevated levels of Met or HGF expression.

METHODS: Met expression and copy number was determined by ELISA and qPCR, HGF mRNA by RT-qPCR. Adult GBM tumor xenografts were grown subcutaneously in athymic BALB/c mice. After tumor size reached 200-500 mm3 subcutaneously, groups of 10 mice were randomly treated with either drug vehicle/control or INC280 (10mg/kg BID) PO for 30 days. Tumor responses for subcutaneous xenografts were assessed by tumor growth delay and regression.

RESULTS: Based on activation of the c-Met pathway, the following two xenograft lines were selected for treatment with INC280: D-09-0337 MG and D-09-0477 MG. As a single agent, INC280 demonstrated statistically significant (p<0.001) growth delays of 40.23 and 30.13 days in D-09-0337 MG and D-09-0477 MG, respectively. In addition, when treated with INC280, tumors implanted with D-09-0337 MG (10 out of 10) or D-09-0477 MG (4 out of 10) regressed.

CONCLUSION: Our results demonstrate the therapeutic efficacy of the inhibition of a c-Met receptor tyrosine kinase in adult brain tumor xenografts with activation of the c-Met pathway. These results warrant further exploration of INC280 in clinical trials for the treatment of adult brain tumor patients with dysregulated proto-oncogene c-Met and its ligand HGF.

Citation Format: Stephen T. Keir, Martin A. Roskoski, Sabrina Wagner, Ralph Tiedt, Darell D. Bigner, Henry S. Friedman. Antitumoral activity of INC280 against adult glioblastoma brain tumors xenografts. [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 2079. doi:10.1158/1538-7445.AM2013-2079