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

基本信息

批准号：
8501801
负责人：
Michael Birrer
金额：
$ 39.06万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-03-01 至 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8501801
关键词：
5q31 5q34 5q35.2 5q35.3 Biological Biological Markers Biology Bone Development Cancer Etiology Cancer Patient Cancer cell line Carcinoma Cartilage 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 Profiling Genes Genetic Transcription Genome 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 Molecular Profiling Multi-Institutional Clinical Trial Mus Neoplasm Metastasis Outcome Ovarian PECAM1 gene Pathogenesis Patients Peritoneal Production Property Protein Family Proteins Protocols documentation Regimen Regression Analysis Role SCID Mice Serous Signal Transduction Specimen Staging Staining method Stains Stromal Cells Survival Rate Technology Therapeutic Umbilical vein United States Up-Regulation Validation Woman Xenograft Model Xenograft procedure angiogenesis base cancer cell cancer therapy cell transformation clinical application clinically relevant clinically significant comparative genomic hybridization cytokine fibroblast growth factor 18 gene discovery gene function genome wide association study in vivo knock-down macrophage member migration neoplastic cell new therapeutic target novel novel therapeutic intervention novel therapeutics ovarian neoplasm overexpression prognostic public health relevance receptor therapeutic target tumor tumorigenesis validation studies

项目摘要

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）：上皮卵巢癌是女性与癌症相关死亡的第五个主要原因，并且在妇科癌症中的病例竞选率最高。高通量基因组技术（例如基因表达分析）为卵巢癌提供了新的生物标志物和潜在的新型治疗靶标。但是，需要对生物学水平和临床水平的全面功能验证研究，以更好地了解这些生物标志物的机理基础，并实现它们的临床意义和应用。成纤维细胞生长因子18（FGF18）最近被确定为表达签名中异常表达的基因，可预测晚期浆液性卵巢癌患者的生存率较差。此外，已证明FGF18和FGFR4的基因组扩增可预测患有晚期高级浆液卵巢癌女性的总体生存率差。但是，尚未确定FGF18/FGFR4在卵巢癌的临床病理特性中的确切作用。初步研究表明，FGF18促进了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，FGF18卵巢癌细胞中的表达导致肿瘤形成增加。微阵列分析表明，FGF18对大量促炎性细胞因子的上调可能介导FGF18表达异种移植物中的巨噬细胞的血管生成和浸润的增加。该建议假设FGF18/FGFR4扩增和过表达显着调节恶性上皮细胞和肿瘤基质细胞，随后导致患者的生存率较差。该项目将使用大量多中心临床试验标本（GOG218）（GOG218）验证FGF18/FGFR4轴的预后价值，并在卵巢肿瘤细胞中和卵巢肿瘤细胞中的FGF18的功能作用和信号网络描述。。最后，最近开发的FGF陷阱蛋白（来自五个Prime Therapeutics Inc.）将被用作原理的证明，将FGF18作为针对上皮卵巢癌的新型治疗干预措施。