Abstract
INTRODUCTION: EMD1214063 is a MET tyrosine kinase inhibitor with the potential for antineoplastic activity. Selectively binding to MET tyrosine kinase, EMD1214063 disrupts MET signal transduction pathways which may induce apoptosis in tumor cells overexpressing this kinase. The receptor tyrosine kinase MET is the product of the proto-oncogene c-Met and is overexpressed or mutated in many tumor cell types; this protein plays key roles in tumor cell proliferation, survival, angiogenesis and metastasis. As a part of this study, we looked at the combination of EMD1214063 with Bevacizumab (BEV). METHODS: Subcutaneous (08-0357 and 09-0477) and intracranial (09-0477) brain tumor xenografts were grown in athymic BALB/c mice. These xenograft lines were selected for treatment based on phospho-MET, total MET, HGF mRNA, and MET copy number expression. After tumor size reached 200-500 mm3 subcutaneously or 3 days after intracranial implantation, groups of 8-10 mice were stratified into the following groups: control, EMD1214063 alone, BEV alone, and EMD1214063 + BEV. RESULTS: For 08-0537 the combination of EMD1214063 + BEV produced a 12.06 day delay (P < 0.004), however, the additive effect of BEV alone + EMD1214063 alone was 13.97 days. For 09-0477, using a subcutaneous model, EMD1214063 alone produced a 26.41 day delay (P < 0.001) and the combination with BEV delayed tumor growth by 43.01 days (P < 0.001). The additive effect of single agents was 29.39 days. Intracranially, EMD1214063 alone increased survival by 56% (P < 0.023) and when combined with BEV survival increased to 180% (P < 0.001) The additive effect of single agents was an 88% increase in survival. CONCLUSION: Our studies confirm that EMD1214063 in combination with BEV is active against GBM in both subcutaneous and intracranial models. Furthermore, the data indicates that EMD1214063 is also active as a monotherapy in specific xenograft lines. The driver of single agent activity may be related to HGF expression.