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

描述(申请人提供)：上皮性卵巢癌是女性癌症相关死亡的第五大原因，是妇科癌症中病死率最高的。基因表达谱等高通量基因组技术为卵巢癌提供了新的生物标志物和潜在的治疗靶点。然而，需要在生物学和临床水平上进行全面的功能验证研究，以更好地了解这些生物标志物的机制基础，并认识到它们的临床意义和应用。成纤维细胞生长因子18(FGF18)最近被发现是晚期浆液性卵巢癌患者中一种异常表达的基因，其表达特征预示着晚期浆液性卵巢癌患者的低生存率。此外，FGF18和FGFR4的基因组扩增已被证明可以预测晚期高级别浆液性卵巢癌患者的总体生存率较低。然而，FGF18/FGFR4在卵巢癌临床病理特性中的确切作用尚未确定。初步研究表明，FGF18可促进卵巢癌细胞和血管内皮细胞的体外迁移和侵袭。在SCID小鼠异种移植模型中，FGF18在卵巢癌细胞中的表达导致肿瘤形成增加。基因芯片分析显示，FGF18上调了大量促炎细胞因子的表达，这可能是表达FGF18的异种移植瘤血管生成增加和巨噬细胞浸润的原因之一。这一建议假设FGF18/FGFR4的扩增和过度表达显着调节恶性上皮细胞和肿瘤间质细胞，从而导致患者较差的生存。本项目将使用大量多中心临床试验标本(GOG218)来验证FGF18/FGFR4轴的预后价值，并在体内外描绘FGF18在卵巢肿瘤细胞和卵巢肿瘤间质细胞中的功能作用和信号网络。最后，最近开发的成纤维细胞生长因子陷阱蛋白(来自Five Prime Treateutics Inc.)将被用作以FGF18为靶点作为治疗上皮性卵巢癌的新的治疗干预措施的原则证据。

DESCRIPTION (provided by applicant): 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.