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：
8505413
负责人：
ANDREW M LOWY
金额：
$ 27.55万
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/8505413
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 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 cancer cell cancer therapy carcinogenesis gemcitabine in vivo new therapeutic target novel oncogene addiction overexpression pancreatic cancer cells pancreatic neoplasm promoter receptor receptor downregulation response therapeutic target tumor tumor microenvironment tumor progression

项目摘要

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.

描述（由申请人提供）：胰腺癌患者持续的惨淡结果表明我们未能理解对肿瘤进展和生存至关重要的分子机制。我们的小组和其他人确定 RON 酪氨酸激酶受体是一种过度表达的蛋白质，也是胰腺癌的潜在新治疗靶点。我们实验室的工作假设是，RON 受体信号传导是人类胰腺癌侵袭性生长和存活的有效促进剂，代表了潜在有价值的治疗靶点。为了支持这一观点，我们最近证明 RON 受体下调可以使体内胰腺癌细胞对吉西他滨敏感。最近的出版物也证实了 RON 与胰腺癌的相关性，记录了 RON 是胰腺癌中常见的过度表达蛋白，可能在 KRAS 癌基因成瘾的情况下介导细胞存活。我们自己的初步工作表明，在小鼠中，仅 RON 过度表达就可以介导胰腺癌发生，并且在致癌性 Kras 的情况下，它可能会加速癌发生。尽管有这些发现，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。该应用程序的目标是； 1) 直接检验 RON 信号传导促进胰腺上皮内瘤变进展为胰腺癌的假设，2) 研究胰腺癌中 RON 配体依赖性和配体非依赖性激活的机制，3) 测试新型 RON 单克隆抗体的效果研究人员对源自患者的胰腺癌异种移植物的原位生长进行研究，以确定与激活的 RON 信号传导和癌基因成瘾相关的生物标志物。这些研究的结果将增强我们对 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。