Neurotensin in Fibrolamellar Liver Cancer

神经降压素在纤维板层肝癌中的作用

基本信息

  • 批准号:
    9176932
  • 负责人:
  • 金额:
    $ 16.8万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-07-15 至 2018-06-30
  • 项目状态:
    已结题

项目摘要

Project Summary/Abstract Fibrolamellar hepatocellular carcinoma (FL-HCC) is a form of primary liver cancer that afflicts healthy children and young adults without underlying liver disease; approximately 90% of HCCs in this age group are FL-HCCs. HCC as a whole is a remarkably diverse disease from a histologic and molecular standpoint, and in the vast majority of adult cases arises in the setting of chronic liver injury and cirrhosis. Conversely, FL-HCCs display consistent clinical behavior and have a homogeneous histologic appearance, but there are no known risk factors. FL-HCC also differs from other subtypes of HCC in that it arises in normal liver, and since these patients are healthy at baseline, they tend to present with advanced disease, leaving no options for cure. Currently there are no effective non- surgical therapies for patients with FL-HCC. Therefore we aim to develop targeted therapies for FL- HCC patients through a detailed understanding of the molecular pathogenesis of this disease. Recently, a putative causative mutation in FL-HCC was reported, and results in a chimeric transcript consisting of the promoter region and first exon of a gene encoding a heat shock protein (DNAJB1) fused to the majority of the sequence for the gene encoding the catalytic subunit of protein kinase A (PRKACA). The mechanisms by which the resultant fusion protein drives carcinogenesis remain unknown, though we have recently demonstrated increased PKA activity in FL-HCCs compared to normal livers. The current proposal outlines experiments that will further investigate drivers of excess PKA signaling in FL-HCC, with focus on the role of a neuroendocrine hormone in this disease. Specifically, we will 1) evaluate the contribution of neurotensin to the development of FL-HCC, 2) investigate how the DNAJB1-PRKACA fusion leads to neuroendocrine activation in these cancers, and 3) define the oncologic effects of neurotensin/PKA signaling in the liver. In summary, we propose to investigate the mechanisms by which the DNAJB1-PRKACA protein product synergizes with neurotensin to drive carcinogenesis in FL-HCC, paving the way for the development of targeted therapies for this cancer.
项目总结/文摘

项目成果

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KIMBERLY J RIEHLE其他文献

KIMBERLY J RIEHLE的其他文献

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{{ truncateString('KIMBERLY J RIEHLE', 18)}}的其他基金

Neurotensin in Fibrolamellar Liver Cancer
神经降压素在纤维板层肝癌中的作用
  • 批准号:
    9316571
  • 财政年份:
    2016
  • 资助金额:
    $ 16.8万
  • 项目类别:

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