RON Receptor in Pancreatic Cancer Biology and Therapy

描述(由申请人提供)：胰腺癌患者持续的惨淡结局揭示了我们未能理解对肿瘤进展和生存至关重要的分子机制。我们的团队和其他人发现RON酪氨酸激酶受体是胰腺癌中一种过表达的蛋白质和潜在的新治疗靶点。我们实验室的工作假设是，RON受体信号是人胰腺癌侵袭性生长和生存的有力促进因素，具有潜在的有价值的治疗靶点。为了支持这一观点，我们最近在体内表明，RON受体下调可以使胰腺癌细胞对吉西他滨敏感。RON与胰腺癌的相关性也被最近的文献所证实，它是胰腺癌中一种常见的过表达蛋白，可能在KRAS癌基因成瘾的背景下调节细胞生存。我们自己的初步工作表明，在小鼠中，RON的过度表达可以单独介导胰腺癌的发生，并可能在致癌Kras的背景下加速癌症的发生。尽管有这些发现，但我们对RON受体生物学及其在胰腺癌发生中的作用的理解仍然存在重大差距。这项应用的目的是：1)直接验证RON信号促进胰腺上皮内瘤变向胰腺癌进展的假设，2)研究RON配体依赖和配体非依赖激活在胰腺癌中的机制，3)测试新型Ron单抗对患者来源的胰腺癌移植瘤原位生长的影响，以确定与激活的RON信号和癌基因成瘾相关的生物标志物。这些研究的结果将加强我们对RON生物学的理解，从而为胰腺癌RON导向疗法的开发和进一步测试提供信息。

DESCRIPTION (provided by applicant): The continued dismal outcomes for pancreatic cancer patients reveal our failure to understand molecular mechanisms critical to tumor progression and survival. Our group and others identified the RON tyrosine kinase receptor as an overexpressed protein and potential novel therapeutic target in pancreatic cancer. The working hypothesis of our laboratory is that RON receptor signaling is a potent promoter of invasive growth and survival in human pancreatic cancer that represents a potentially valuable therapeutic target. In support of this idea, we have recently shown that RON receptor downregulation can sensitize pancreatic cancer cells to gemcitabine in vivo. The relevance of RON to pancreatic cancer has also been borne out by recent publications documenting it as a commonly overexpressed protein in pancreatic cancer that may mediate cell survival in the setting of KRAS oncogene addiction. Our own preliminary work suggests that in the mouse, RON overexpression alone can mediate pancreatic carcinogenesis and that it may accelerate carcinogenesis in the setting of oncogenic Kras. Despite these findings, major gaps in our understanding of RON receptor biology and its role in pancreatic carcinogenesis remain. The goals of this application are; 1) to directly test the hypothesis that RON signaling promotes progression of pancreatic intraepithelial neoplasia to pancreatic cancer, 2) to investigate mechanisms of RON ligand dependent and ligand independent activation in pancreatic cancer and, 3) to test the effects of a novel RON monoclonal antibody on the orthotopic growth of patient-derived pancreatic cancer xenografts in order to identify biomarkers associated with activated RON signaling and oncogene addiction. The findings from these studies will enhance our understanding of RON biology and thereby serve to inform the development and further testing of RON-directed therapies in pancreatic cancer.