Effect of the orally available MET inhibitor PF-2341066 on tumor burden and metastasis in an orthotopic xenograft model of bladder cancer.

Abstract

263 Background: Met over-expression has been found in bladder cancer (CaB). However, to date, the effects of Met inhibition in CaB have not been reported. We used a small, orally available, highly specific Met-inhibitor currently on phase 2 clinical trials, to assess its effects in an orthotopic xenograft model of bladder transitional cell carcinoma (TCC). Methods: An orthotopic xenograft murine model of TCC of the bladder was developed with T24-Luciferase positive bladder cancer cells. NIH 3T3 cells producing human hepatocyte growth factor (hHGF) were implanted subcutaneously in mice to provide a source of hHGF. Animals were treated with the selective Met inhibitor (PF-2341066) intra-peritoneally after positive detection of bladder tumor primary and/or metatastatic disease. Fluorescence imaging (Xenogen IVIS) of mice was performed weekly. Mice were euthanized 4 weeks after the start of treatment and their tissues studied histologically. Results: PF-2341066 was found to reduce tumor burden to below detectable levels in both primary and metastatic sites in all mice treated. No noticeable side effects were detected in treated mice secondary to drug administration. Conclusions: This study is the first to test a small orally available Met-selective inhibitor in an orthotopic, HGF-driven model of human CaB. Our results demonstrate that Met-inhibition by PF-2341066 reduces TCC tumor burden supporting its potential use in patients with bladder cancer. No significant financial relationships to disclose.