RON Receptor in Pancreatic Cancer Biology and Therapy

项目摘要 胰腺癌患者持续的令人沮丧的结果揭示了我们对分子生物学的理解的失败。 对肿瘤进展和存活至关重要的机制。我们的团队和其他人鉴定了罗恩酪氨酸 激酶受体在胰腺癌中作为过表达蛋白和潜在的新治疗靶点。的 我们实验室的工作假设是罗恩受体信号传导是侵袭性生长的有效促进剂， 人胰腺癌的存活率，代表了潜在的有价值的治疗靶点。为支持这一 我们最近发现，罗恩受体下调可以使胰腺癌细胞对 体内吉西他滨。罗恩与胰腺癌的相关性也被最近的研究所证实。 文献记载它是胰腺癌中通常过表达的蛋白质，可能介导细胞凋亡。 在KRAS癌基因成瘾的情况下生存。我们自己的初步研究表明，在小鼠中， 罗恩过表达可单独介导胰腺癌的发生，并可能加速胰腺癌的发生 在致癌Kras基因的背景下。尽管有这些发现，但我们对罗恩受体的理解中的主要差距 生物学及其在胰腺癌发生中的作用仍然存在。该应用程序的目标是：1）直接测试 罗恩信号转导促进胰腺上皮内瘤变向胰腺癌进展假说 2）研究罗恩配体依赖性和配体非依赖性激活的机制， 胰腺癌，以及3）测试新的罗恩单克隆抗体对胰腺癌原位生长的影响。 患者来源的胰腺癌异种移植物，以鉴定与活化的罗恩相关的生物标志物 信号传导和癌基因成瘾。这些研究结果将有助于加深我们对罗恩的认识 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.