RON Receptor in Pancreatic Cancer Biology and Therapy

项目摘要 胰腺癌患者持续的悲观结局表明我们无法理解分子 肿瘤进展和生存的关键机制。我们的团队和其他人发现了Ron酪氨酸 蛋白激酶受体作为胰腺癌高表达蛋白和潜在的新治疗靶点。这个 我们实验室的工作假说是，RON受体信号是侵袭性生长和 人类胰腺癌的存活率代表了一个潜在的有价值的治疗目标。为了支持这一点 最近，我们发现RON受体的下调可以使胰腺癌细胞对 吉西他滨在体内。RON与胰腺癌的相关性也在最近的研究中得到证实 文献报道，它是胰腺癌中一种常见的过度表达的蛋白，可能介导细胞 在KRAS癌基因成瘾的背景下存活。我们自己的初步工作表明，在老鼠身上， RON单独过表达可介导胰腺癌的发生，并可能加速胰腺癌的发生 在致癌克拉斯的背景下。尽管有这些发现，但我们对RON受体的理解存在主要差距 生物学及其在胰腺癌发生中的作用仍然存在。此应用程序的目标是：1)直接测试 RON信号促进胰腺上皮内瘤变向胰腺进展的假说 肿瘤，2)研究RON配体依赖和非配体依赖的激活机制。 3)检测新型RON单抗对人胰腺癌原位生长的影响。 患者来源的胰腺癌移植瘤识别与活化RON相关的生物标记物 信号和癌基因成瘾。这些研究的结果将加深我们对RON的了解 生物学，从而为RON导向疗法的开发和进一步测试提供信息 胰腺癌。

PROJECT ABSTRACT 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.