RON Receptor in Pancreatic Cancer Biology and Therapy

胰腺癌生物学和治疗中的 RON 受体

基本信息

批准号：
8337316
负责人：
ANDREW M LOWY
金额：
$ 27.7万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-22 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8337316
关键词：
Apoptotic Autocrine Communication Automobile Driving Biological Markers Biology Cancer Biology Cancer Patient Cell Death Cell Survival Development Event Failure Frustration Goals Growth Human In Vitro Insulin-Like-Growth Factor I Receptor KRAS2 gene Laboratories Ligands Malignant Neoplasms Malignant neoplasm of pancreas Mediating Molecular Monoclonal Antibodies Mouse Strains Mus Oncogenes Oncogenic Outcome Pancreas Pancreatic Intraepithelial Neoplasia Patients Penetration Pharmacotherapy Protein Isoforms Proteins Publications Receptor Protein-Tyrosine Kinases Receptor Signaling Refractory Renal Cell Carcinoma Role Science Signal Transduction System Testing Transgenic Mice Work Xenograft procedure addiction cancer cell cancer therapy carcinogenesis gemcitabine in vivo new therapeutic target novel overexpression pancreatic cancer cells pancreatic neoplasm promoter receptor receptor downregulation response therapeutic target tumor tumor progression

项目摘要

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.

项目摘要胰腺癌患者持续的惨淡结果表明我们未能理解分子生物学对肿瘤进展和生存至关重要的机制。我们的小组和其他人鉴定了 RON 酪氨酸激酶受体作为胰腺癌中过度表达的蛋白质和潜在的新治疗靶点。这我们实验室的工作假设是 RON 受体信号传导是侵袭性生长和人类胰腺癌的存活率是一个潜在有价值的治疗目标。为了支持这一点我们最近证明 RON 受体下调可以使胰腺癌细胞对吉西他滨在体内。最近的研究也证实了 RON 与胰腺癌的相关性出版物将其记录为胰腺癌中常见的过度表达蛋白，可能介导细胞 KRAS 致癌基因成瘾环境中的生存。我们自己的初步工作表明，在小鼠中， RON 过表达单独可介导胰腺癌发生，并可能加速癌发生在致癌克拉斯的背景下。尽管有这些发现，我们对 RON 受体的理解仍存在重大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）直接测试假设 RON 信号传导促进胰腺上皮内瘤变进展为胰腺癌症，2) 研究 RON 配体依赖性和配体非依赖性激活的机制胰腺癌，3) 测试新型 RON 单克隆抗体对原位生长的影响患者来源的胰腺癌异种移植物，以确定与激活的 RON 相关的生物标志物信号传导和癌基因成瘾。这些研究结果将增强我们对 RON 的理解生物学，从而为 RON 导向疗法的开发和进一步测试提供信息胰腺癌。