Abstract
Abstract Introduction and Objective: Mutations in the FGFR3 gene, which can confer constitutive activity, are found in up to 80% of low grade papillary bladder cancers (BC). Overexpression of FGFR3 has been detected in approximately half of high grade and invasive tumors. In this study we evaluate FGFR3 in a cohort of American patients and investigate the effect of targeting FGFR3 in pre-clinical models of bladder cancer. Materials and Methods: DNA was extracted from 170 fresh frozen BC specimens using a commercial kit and PCR of exons 7 and 10 was performed. Mutation analysis was performed by ABI Big Dye Terminator Cycle Sequencing. FGFR3 expression was analyzed by immunohistochemistry in an overlapping cohort of 143 patients with BC. FGFR3 expression, phosphorylation and downstream signaling were measured in a panel of BC cell lines, and the efficacy of two small molecule inhibitors (TKI258 and BGJ398) was tested on signaling and 3H-thymidine incorporation. A specific inhibitory monoclonal antibody targeting FGFR3 was evaluated in an orthotopic xenograft model of BC. Tumor burden was measured with bioluminescent imaging. Results: FGFR3 mutations were identified in 44 (26%) BC samples, including 28/50 (56%) of low grade papillary lesions. Overexpression of FGFR3 was noted in 53% of all BC specimens regardless of stage and grade, but not in normal urothelium. FGFR3 inhibition effectively abrogated constitutive phosphorylation of FGFR3 and p42/44MAPK in a subset of bladder cancer cell lines. A growth inhibitory effect was observed in the same cell lines. The growth of UC14 xenografts in the bladder of nude mice was inhibited by 40%. Conclusion: These studies underline the potential clinical relevance of FGFR3 mutation and expression in bladder cancer. Furthermore, the preclinical investigations offer proof of principle for moving forward with clinical trials studying the administration of specific FGFR3 inhibitors in patients with bladder cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 234. doi:10.1158/1538-7445.AM2011-234
Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
