Epithelial ovarian cancer is the fifth leading cause of cancer-related death among woman and has the highest case-fatality rate among gynecologic cancers. High throughput genomic technologies such as gene expression profiling have provided 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. However, the exact role of FGF18/FGFR4 in the clinicopathologic properties of ovarian cancer has not been determined. Preliminary studies 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 demonstrated 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. This proposal hypothesizes that FGF18/FGFR4 amplification and overexpression significantly modulates both the malignant epithelial and tumor stromal cells which subsequently leads to poorer patient survival. This project will validate the prognostic value of FGF18/FGFR4 axis using a large collection of multi-center clinical trial specimens (GOG218) and delineate the functional role and signaling network of FGF18 in ovarian tumor cells and ovarian tumor stromal cells in vitro and in vivo. Finally, the recently developed FGF trap proteins (from Five Prime Therapeutics Inc.) will be used as proof of principle to target FGF18 as a novel therapeutic intervention against epithelial ovarian cancer.
This grant proposes to investigate FGF18/FGFR4 as novel therapuetic biomarkers for ovarian cancer using large number of prospectively collected specimens. Gene function analysis will be performed to understand the biology and mechanisms of FGF18/FGFR4 in ovarian cancer pathogenesis. This proposed study if successful will contribute the development of new therapeutic regimens for ovarian cancer treatment.
|Leung, Cecilia S; Yeung, Tsz-Lun; Yip, Kay-Pong et al. (2014) Calcium-dependent FAK/CREB/TNNC1 signalling mediates the effect of stromal MFAP5 on ovarian cancer metastatic potential. Nat Commun 5:5092|
|Wei, Wei; Mok, Samuel C; Oliva, Esther et al. (2013) FGF18 as a prognostic and therapeutic biomarker in ovarian cancer. J Clin Invest 123:4435-48|