Abstract 1072: The FGF18/FGFR4 amplicon: Novel therapeutic biomarkers for ovarian cancer

Abstract

Abstract Epithelial ovarian cancer is the fifth leading cause of cancer-related death among women and has the highest case-fatality rate among gynecologic cancers. High throughput genomic technologies have been instrumental in identifying new biomarkers and potential novel therapeutic targets for ovarian cancer. However, comprehensive functional validation studies on both the biological and clinical levels are needed to better understand the mechanistic basis for these biomarkers and realize their clinical significance and application. Fibroblast growth factor 18 (FGF18) has been recently identified as an aberrantly expressed gene within an expression signature predicting poor rate of survival in patients with advanced stage serous ovarian cancers. In addition, genomic amplification of both FGF18 and FGFR4 has been shown to predict for poor overall survival among women with advanced stage high grade serous ovarian cancers. siRNA mediated knock-down of FGFR4 abolishes FGF18 induced phosphorylation of FRS2 and ERK1/2 in ovarian cancer cells, indicating the FGF18 signaling is at least partially conferred by FGFR4 in ovarian cancer cells. However, the exact role of FGF18/FGFR4 in the clinicopathologic properties of ovarian cancer has not been determined. Preliminary studies by ectopic FGF18 overexpression or recombinant FGF18 treatment demonstrate that FGF18 promotes the in vitro migration and invasion of both ovarian cancer cells and endothelial cells. In SCID mice xenograft models, FGF18 expression in ovarian cancer cells results in increased tumor formation. Microarray analysis identified up-regulation of a large number of proinflammatory cytokines by FGF18 which may mediate the increases in angiogenesis and infiltration of macrophages seen in FGF18 expressing xenografts. Pathway analysis further demonstrated participation of NF-κB signaling in FGF18 mediated cytokine production. Conversely, knock-down of FGF18 in ovarian cancer cells reduces the in vitro migration; inhibits the production of cytokines and impairs the in vivo tumorigenicity in SCID mice xenograft model. Taken together, FGF18/FGFR4 axis may play an important role in ovarian cancer pathogenesis and may serve as a novel therapeutic target. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1072. doi:1538-7445.AM2012-1072