Effect of modulation of MET with the small molecule inhibitor PF-04217903 on osteosarcoma metastasis in vivo.

Abstract

9567 Background: MET is a tyrosine kinase receptor that is important for normal cell growth and migration. Activating alterations have also been found in several carcinomas. Previous studies in our laboratory have found high levels of MET in 85% of osteosarcoma samples. Both pharmacologic and genetic modulation of MET resulted in a decrease in multiple in vitro parameters of the metastatic phenotype in some osteosarcoma cell lines. PF-04217903 is a novel small molecule tyrosine kinase inhibitor that targets MET and is currently in clinical trials. The results of in vitro testing led us to test the effectiveness of PF-04217903 as an anti-metastatic agent in vivo. Methods: Two highly metastatic osteosarcoma cell lines were injected by tail vein into immunodeficient mice (MNNG-HOS which has constitutively activated MET and MG63.2 which has high levels of total and phospho-MET). Mice were treated with PF-04217903 (30 mg/kg) or vehicle control by gavage 5 days on and 2 days off and euthanized on day 30. Results: For MNNG-HOS, the average number of visible surface nodules in control mice was 4.8 (SD 2.3). Mice treated with PF- 04217903 had a ten-fold reduction in the number of metastatic nodules (average 0.4, SD 0.7, p=0.0001). This treated cohort included 6 out of 9 mice with no visible nodules. Mice injected with MG63.2 cells and treated with PF-04217903 had a 37% reduction in nodules (p=0.016) compared to control mice. Conclusions: Mice treated with the small molecule MET inhibitor PF-04217903 showed a decreased number of metastatic lung nodules in two osteosarcoma cell lines, one with MET activation and one with high-level MET expression. We are currently studying the mechanism by which MG63.2 cells have high levels of MET. These data suggest a potential role for MET inhibition in the treatment of patients with metastatic osteosarcoma. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer