Abstract 5807: The dual c-Met/VEGFR2 inhibitor foretinib augments chemotherapy response in preclinical models of gastric cancer

Abstract

Abstract BACKGROUND: Gastric adenocarcinoma (GAC) is the fourth most common malignant tumor in the world. Several growth factors and their receptors including c-Met and VEGFR, are overexpressed in GAC and thus provide a potentially effective therapeutic target. Foretinib is a novel small molecule inhibitor of the c-Met and VEGFR pathways. We evaluated the therapeutic efficacy of foretinib to enhance the antitumor response of nab-paclitaxel (NPT), a water-soluble albumin-bound formulation of paclitaxel, or oxaliplatin in preclinical models of GAC. METHODS: Tumor growth experiments were performed in subcutaneous xenografts in NOD/SCID mice using 5x106 MKN-45 cells. Animal survival study was performed as peritoneal dissemination model in NOD/SCID mice using 10x106 MKN-45 cells. The mechanistic evaluation involved immunohistochemical and Immunoblot analyses. RESULTS: In subcutaneous GAC xenografts, NPT and foretinib monotherapies demonstrated inhibition in tumor growth, while NPT plus foretinib combined showed additive effects. Net tumor growth in different therapy groups was 581.7 mm3 in controls, 397.9 mm3 after oxaliplatin, 229.9 mm3 after NPT, -82.6 mm3 (tumor regression) after foretinib, -74.1 mm3 after oxaliplatin+foretinib and -96.3 mm3 after NPT+foretinib. No significant change in body weight was observed for those mice treated with nab-paclitaxel, oxaliplatin or foretinib. In the GAC survival model, median animal survival compared to controls (23 days) remained unchanged after oxaliplatin therapy (24 days, p=ns) but increased after monotherapy with NPT (42 days, an 83% increase, p=0.0014) or foretinib (46 days, a 100% increase, p=0.0006). Importantly, a further increase in animal survival was observed in combination therapy groups: oxaliplatin+foretinib (55 days, a 139% increase, p=0.0006) and NPT+foretinib (76 days, 230% increase, p=0.0006). Effects of therapy on intratumoral proliferation and microvessel density corresponded with tumor growth inhibition data. In vitro studies demonstrated inhibition in the proliferation of GAC cells by both NPT and foretinib, with additive effects in combination. Immunoblot analysis revealed that foretinib pre-exposure blocked HGF-induced expression of phospho-c-Met. Furthermore, the foretinib treatment caused a decrease in phosphorylation of AKT, ERK, and PLC-γ in GAC cells, either alone or in combination with nab-paclitaxel. CONCLUSION: These findings suggest that the antitumor effect of chemotherapy can be significantly enhanced by the c-Met/VEGFR pathway inhibitor foretinib, which might lead to clinically relevant therapeutic combinations to increase survival of GAC patients. Citation Format: Niranjan Awasthi, Meghan Grojean, Sheena Monahan, Sazzad Hassan, Urs von Holzen, Margaret A. Schwarz, Roderich E. Schwarz. The dual c-Met/VEGFR2 inhibitor foretinib augments chemotherapy response in preclinical models of gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5807.