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

描述（由申请人提供）：上皮性卵巢癌是女性癌症相关死亡的第五大原因，在妇科癌症中病死率最高。高通量基因组学技术如基因表达谱分析为卵巢癌提供了新的生物标志物和潜在的新的治疗靶点。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，并实现其临床意义和应用。成纤维细胞生长因子18（FGF 18）最近被鉴定为一个表达特征中的异常表达基因，预测晚期浆液性卵巢癌患者的生存率低。此外，FGF 18和FGFR 4的基因组扩增已被证明可预测晚期高级别浆液性卵巢癌妇女的总体生存率较差。然而，FGF 18/FGFR 4在卵巢癌的临床病理学特性中的确切作用尚未确定。初步研究表明，FGF 18促进卵巢癌细胞和内皮细胞的体外迁移和侵袭。在SCID小鼠异种移植模型中，卵巢癌细胞中的FGF 18表达导致肿瘤形成增加。微阵列分析表明，FGF 18上调了大量的促炎细胞因子，这可能介导在表达FGF 18的异种移植物中观察到的血管生成和巨噬细胞浸润的增加。该提议假设FGF 18/FGFR 4扩增和过表达显著调节恶性上皮细胞和肿瘤基质细胞，其随后导致较差的患者存活。本项目将利用大量多中心临床试验标本（GOG 218）验证FGF 18/FGFR 4轴的预后价值，并在体外和体内阐明FGF 18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FGF陷阱蛋白（来自Five Prime Therapeutics Inc.）将用作靶向FGF 18作为针对上皮性卵巢癌的新型治疗干预的原理证明。

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.