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

基本信息

  • 批准号:
    10251133
  • 负责人:
  • 金额:
    $ 32.1万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-09-10 至 2023-08-31
  • 项目状态:
    已结题

项目摘要

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 -项目概要 总体目标是了解和定义有助于细胞的机制, 胆管癌的发展和进展,称为胆管癌(CCA)。CCA研究进展 治疗将需要对分子信号通路的理解和靶向药物的验证 与用于患者选择的生物标志物结合。Hippo和成纤维细胞生长因子受体2(FGFR 2) 信号传导途径被认为是CCA中的致癌介质。在这个应用程序中,我们统一了这些 通过在CCA中设定Hippo和FGFR 2信号传导通路之间的串扰来观察。符合 这个概念,我们已经产生了初步的数据表明,通过激活海马信号, 转录共激活因子YES相关蛋白(雅普)驱动FGFR 2的表达,并进而驱动FGFR 2的表达 信号传导介导雅普活化。对该途径的进一步评估表明, 雅普,其似乎依赖于Src家族激酶(SFK)。酪氨酸磷酸化的雅普依次 与TBX 5相关,驱动致癌转录活性。从临床前治疗的角度来看, FGFR 2信号传导的抑制在具有雅普核的患者来源的异种移植物中诱导肿瘤细胞死亡 但在Hippo通路信号传导的这种标志物阴性的那些中没有。基于这些 根据初步数据,我们提出了一个中心假设,即CCA进展可以由FGFR 2介导的 SFK引起的雅普酪氨酸磷酸化。我们现在将使用电流和互补分子, 生物化学和细胞生物学方法以及临床前CCA模型来检验这一假设。我们 具体目标将检验三个假设。首先,雅普驱动特定的FGFR 2表达,而FGFR 2表达反过来又 (a)FGFR介导的SFK活化和雅普酪氨酸磷酸化;和 (b)酪氨酸磷酸化的雅普与TBX 5介导的FGFR转录表达共激活 家庭成员第二,通过雅普核定位作为对FGFR 2 - 1应答的生物标志物, 靶向治疗:(a)用FGFR抑制剂治疗的来自患者的异种移植物(PDX);和(B)用FGFR抑制剂治疗的来自患者的异种移植物(PDX);和 结合PDX中雅普激活特征的证据。最后,FGFR信号的抑制是 在患有CCA的患者中的治疗性:(a)在接受FGFR 2融合阴性/雅普核阳性CCA的患者中, INCB 054828,一种panFGFR抑制剂,在临床试验的背景下;和(B)通过中断Hippo信号传导 途径。该提案在技术和概念上都具有创新性, 确定了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FGFR抑制与生物标志物(即,核雅普定位) 选择.

项目成果

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GREGORY J. GORES其他文献

Orthotopic Liver Transplantation for Preoperative Early-Stage Hepatocellular Carcinoma
  • DOI:
    10.1016/s0025-6196(12)62240-x
  • 发表时间:
    1994-06-01
  • 期刊:
  • 影响因子:
  • 作者:
    CHEE-KIAT TAN;GREGORY J. GORES;JEFFERY L. STEERS;MICHAEL K. PORAYKO;J. EILEEN HAY;JORGE RAKELA;RUSSELL H. WIESNER;RUUD A.F. KROM
  • 通讯作者:
    RUUD A.F. KROM

GREGORY J. GORES的其他文献

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{{ truncateString('GREGORY J. GORES', 18)}}的其他基金

Cholestatic Liver Injury
胆汁淤积性肝损伤
  • 批准号:
    10372002
  • 财政年份:
    2020
  • 资助金额:
    $ 32.1万
  • 项目类别:
Cholestatic Liver Injury
胆汁淤积性肝损伤
  • 批准号:
    10588191
  • 财政年份:
    2020
  • 资助金额:
    $ 32.1万
  • 项目类别:
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
  • 财政年份:
    2018
  • 资助金额:
    $ 32.1万
  • 项目类别:
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:
    10006083
  • 财政年份:
    2018
  • 资助金额:
    $ 32.1万
  • 项目类别:
Comparative Medicine Core Facility Infrastructure Improvement
比较医学核心设施基础设施改善
  • 批准号:
    7934406
  • 财政年份:
    2010
  • 资助金额:
    $ 32.1万
  • 项目类别:
Enrichment Program
强化计划
  • 批准号:
    10630253
  • 财政年份:
    2009
  • 资助金额:
    $ 32.1万
  • 项目类别:
Enrichment Program
强化计划
  • 批准号:
    10200781
  • 财政年份:
    2009
  • 资助金额:
    $ 32.1万
  • 项目类别:
Enrichment Program
强化计划
  • 批准号:
    10438739
  • 财政年份:
    2009
  • 资助金额:
    $ 32.1万
  • 项目类别:
LONG-ACTING OCTREOTIDE IN THE TREATMENT OF PATIENTS
长效奥曲肽在患者治疗中的应用
  • 批准号:
    7206098
  • 财政年份:
    2005
  • 资助金额:
    $ 32.1万
  • 项目类别:
Organelle Dysfunction and Apoptosis in Liver Epithelia
肝上皮细胞器功能障碍和细胞凋亡
  • 批准号:
    8250599
  • 财政年份:
    2003
  • 资助金额:
    $ 32.1万
  • 项目类别:
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