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

FGF18/FGFR4 扩增子：卵巢癌的新型治疗生物标志物

• 批准号: 9588790
• 负责人: Michael Birrer
• 金额: $ 14.58万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9588790
• 关键词: 5q31; Biological; Biological Markers; Biology; Bone Development; Cancer Etiology; Cancer Patient; Cancer cell line; Carcinoma; Case Fatality Rates; Cell Line; Cessation of life; Chromosomes; Clinical; Clinical Trials; Collection; DNA copy number; Data; Data Set; Development; Diagnosis; Disease; Endothelial Cells; Epithelial ovarian cancer; FGFR1 gene; FGFR4 gene; Fibroblast Growth Factor; Fibroblast Growth Factor Receptors; Gene Dosage; Gene Expression Profile; Gene Expression Profiling; Genes; Genetic Transcription; Genomics; Goals; Grant; Gynecologic Oncology Group; Human; In Vitro; Infiltration; Investigation; Ligands; Malignant Female Reproductive System Neoplasm; Malignant neoplasm of ovary; Mediating; Microarray Analysis; Molecular; Multi-Institutional Clinical Trial; Mus; Neoplasm Metastasis; Outcome; Ovarian; PECAM1 gene; Pathogenesis; Patients; Peritoneal; Physiological; Production; Prognostic Marker; Property; Protein Family; Proteins; Protocols documentation; Regimen; Regression Analysis; Role; SCID Mice; Serous; Signal Transduction; Specimen; Staining method; Stains; Stromal Cells; Stromal Neoplasm; Survival Rate; Technology; Therapeutic; Umbilical vein; United States; Up-Regulation; Validation; Woman; Xenograft Model; Xenograft procedure; angiogenesis; base; cancer cell; cancer therapy; cartilage development; cell transformation; clinical application; clinically relevant; clinically significant; comparative genomic hybridization; cytokine; fibroblast growth factor 18; gene discovery; gene function; genetic signature; genome-wide analysis; in vivo; intraperitoneal; knock-down; macrophage; member; migration; neoplastic cell; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; ovarian neoplasm; overexpression; predictive signature; prognostic value; prospective; public health relevance; receptor; subcutaneous; survival prediction; targeted treatment; therapeutic biomarker; tumor; tumorigenesis; validation studies; whole genome

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.

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。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新治疗靶点。然而，为了更好地了解这些生物标志物的作用机理，认识其临床意义和应用价值，还需要在生物学和临床水平上进行全面的功能验证研究。成纤维细胞生长因子18 （FGF18）最近被发现在预测晚期浆液性卵巢癌患者低生存率的表达特征中是一个异常表达的基因。此外，FGF18和FGFR4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对卵巢癌细胞和内皮细胞的体外迁移和侵袭均有促进作用。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。微阵列分析显示，FGF18上调了大量促炎细胞因子，这可能介导了表达FGF18的异种移植物中血管生成和巨噬细胞浸润的增加。本研究假设FGF18/FGFR4的扩增和过表达显著调节恶性上皮细胞和肿瘤基质细胞，从而导致患者生存率降低。本项目将通过大量多中心临床试验标本（GOG218）验证FGF18/FGFR4轴的预后价值，并在体外和体内描述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FGF陷阱蛋白（来自Five Prime Therapeutics Inc.）将作为FGF18靶点的原理证明，作为一种新的治疗性卵巢癌的干预手段。

项目成果

Mesothelial-to-mesenchymal transition as a possible therapeutic target in peritoneal metastasis of ovarian cancer.

• DOI: 10.1002/path.4889
• 发表时间: 2017-06
• 期刊: The Journal of pathology
• 作者: Rynne-Vidal A;Au-Yeung CL;Jiménez-Heffernan JA;Pérez-Lozano ML;Cremades-Jimeno L;Bárcena C;Cristóbal-García I;Fernández-Chacón C;Yeung TL;Mok SC;Sandoval P;López-Cabrera M
• 通讯作者: López-Cabrera M