Project 2: Therapeutic Inhibition of Fibroblast Growth Factor and YAP Signaling in Cholangiocarcinoma: Preclinical Studies and Clinical Trial

项目2：胆管癌中成纤维细胞生长因子和YAP信号传导的治疗性抑制：临床前研究和临床试验

• 批准号: 10468830
• 负责人: GREGORY J. GORES
• 金额: $ 29.79万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-10 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10468830
• 关键词: Animal Cancer Model; Autocrine Communication; Automobile Driving; Bile duct carcinoma; Biliary Tract Cancer; Biochemical; Biological; Biological Markers; Cancer Biology; Cell Death; Cell Line; Cells; Cholangiocarcinoma; Clinic; Clinical Trials; Coupled; Data; Development; Disease; Evaluation; FGFR2 gene; Family member; Fibroblast Growth Factor; Fibroblast Growth Factor Receptor 2; Fibroblast Growth Factor Receptors; Gene Fusion; Genetic Transcription; Genome; Hepatobiliary; Human; Individual; Interruption; Lead; Ligands; Link; Malignant Neoplasms; Mediating; Mediator of activation protein; Medical; Modeling; Molecular; Nuclear; Nuclear Protein; Nuclear Translocation; Oncogenic; Operative Surgical Procedures; Pathogenesis; Pathway interactions; Patient Selection; Patients; Pre-Clinical Model; Proteins; Signal Pathway; Signal Transduction; Signaling Protein; Stains; Testing; Therapeutic; Transcription Coactivator; Transcriptional Activation; Tyrosine; Tyrosine Phosphorylation; Up-Regulation; Validation; autocrine; base; cancer cell; cancer regression; cancer therapy; immunoreactivity; inhibitor; innovation; intrahepatic cancer; neoplastic cell; novel; novel therapeutic intervention; patient biomarkers; patient derived xenograft model; patient subsets; pre-clinical; preclinical study; protein activation; receptor; response; response biomarker; src-Family Kinases; targeted agent; targeted treatment; therapy outcome; transcriptome; treatment strategy; tumor progression

PROJECT 2 – PROJECT SUMMARY The overall objectives are to understand and define the cellular mechanisms that contribute to the development and progression of biliary tract cancer, termed cholangiocarcinoma (CCA). Advances in CCA therapy will require an understanding of molecular signaling pathways, and validation of targeted agents coupled with biomarkers for patient selection. Both the Hippo and fibroblast growth factor receptor 2 (FGFR2) signaling pathways have been implicated as oncogenic mediators in CCA. In this application, we unify these observations by positing cross-talk between the Hippo and FGFR2 signaling pathways in CCA. Consistent with this concept, we have generated preliminary data demonstrating that Hippo signaling via activation of the transcriptional co-activator YES-associated protein (YAP) drives expression of FGFR2, and in turn FGFR2 signaling mediates YAP activation. Further evaluation of the pathway demonstrates tyrosine phosphorylation of YAP that appears to be dependent on Src family kinases (SFKs). Tyrosine-phosphorylated YAP in turn associates with TBX5, driving oncogenic transcriptional activity. From a pre-clinical therapeutic perspective, inhibition of FGFR2 signaling induces tumor cell death in patient derived xenografts with YAP nuclear immunoreactivity but not in those negative for this marker of Hippo pathway signaling. Based on these preliminary data, we propose the central hypothesis that CCA progression can be driven by FGFR2-mediated YAP tyrosine phosphorylation by SFKs. We will now employ current and complementary molecular, biochemical, and cell biological approaches, and preclinical CCA models to examine this hypothesis. Our specific aims will test three hypotheses. First, that YAP drives specific FGFR2 expression, which in turn promotes YAP signaling by: (a) FGFR-mediated SFK activation and YAP tyrosine phosphorylation; and (b) Tyrosine-phosphorylated YAP co-activated by the TBX5-mediated transcriptional expression of FGFR family members. Second, by that YAP nuclear localization serves as a biomarker for response to FGFR2- targeted therapy: (a) In unselected patient-derived xenografts (PDX) treated with an FGFR inhibitor; and (b) In conjunction with evidence for a YAP activation signature in PDX. Finally, that inhibition of FGFR signaling is therapeutic in patients with CCA: (a) In FGFR2 fusion negative / YAP nuclear positive CCA patients receiving INCB054828, a panFGFR inhibitor, in the setting of a clinical trial; and (b) By interruption of Hippo signaling pathways. The proposal, which is technically and conceptually innovative, is also highly significant because it identifies new mechanisms for CCA oncogenic signaling and will help identify therapeutic strategies for the treatment of CCA, namely FGFR inhibition coupled with a biomarker (i.e., nuclear YAP localization) for patient selection.

项目2--项目总结 总体目标是了解和定义有助于 胆道癌的发生和发展，称为胆管癌(CCA)。CCA研究进展 治疗需要对分子信号通路的了解，以及靶向药物的验证。 再加上用于患者选择的生物标记物。河马和成纤维细胞生长因子受体2(FGFR2) 信号通路被认为是CCA的致癌介质。在本应用程序中，我们统一了这些 通过在CCA中定位河马和FGFR2信号通路之间的串扰来观察。与一致 这个概念，我们已经产生了初步的数据表明，河马信号通过激活 转录共激活因子YAP促进FGFR2的表达，进而促进FGFR2的表达 信号转导YAP的激活。对该途径的进一步评估表明，酪氨酸磷酸化 YAP似乎依赖于Src家族激酶(SFK)。酪氨酸磷酸化的YAP 与TBX5相关，驱动致癌转录活性。从临床前治疗的角度来看， 抑制FGFR2信号通路诱导YAP核移植瘤细胞死亡 但在河马信号通路这一标志阴性的人中不存在免疫反应性。基于这些 初步数据，我们提出了CCA进展可以由FGFR2介导的中心假设 SFKs对YAP酪氨酸的磷酸化作用。我们现在将使用电流和互补分子， 生化和细胞生物学方法，以及临床前CCA模型来检验这一假说。我们的 具体目标将检验三个假设。首先，YAP驱动特定的FGFR2表达，进而 通过以下途径促进YAP信号转导：(A)FGFR介导的SFK激活和YAP酪氨酸磷酸化； (B)Tbx5介导的FGFR转录表达共激活酪氨酸磷酸化的YAP 家庭成员。其次，通过YAP核定位作为对FGFR2反应的生物标志物- 靶向治疗：(A)在未经选择的患者来源的异种移植物(PDX)中使用FGFR抑制剂治疗；和(B)在 与PDX中YAP激活签名的证据相结合。最后，对FGFR信号的抑制是 CCA患者的治疗：(A)FGFR2融合阴性/YAP核阳性的CCA患者接受 INCB054828，一种泛FGFR抑制剂，正在进行临床试验；以及(B)通过中断河马信号 小路。该提案在技术和概念上都是创新的，也具有重要意义，因为它 确定CCA致癌信号的新机制，并将有助于确定治疗策略 CCA的治疗，即抑制FGFR结合生物标志物(即核YAP定位)对患者的治疗 选择。