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：
8234445
负责人：
ANDREW M LOWY
金额：
$ 29.36万
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/8234445
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

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. PUBLIC HEALTH RELEVANCE: The development of successful therapies for pancreatic cancer patients demands a more thorough understanding of the molecular mechanisms that drive tumor progression and survival. Our laboratory recently identified that the majority of pancreatic cancers overexpress the RON receptor tyrosine kinase and that RON signaling promotes pancreatic cancer cell invasive growth and survival. In this proposal, we will investigate how RON becomes activated and ultimately influences invasive growth of pancreatic cancer as well as determine biomarkers that may predict response to RON-directed therapies.

描述（由申请人提供）：胰腺癌患者的持续惨淡结局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酪氨酸激酶受体是胰腺癌中过表达的蛋白质和潜在的新型治疗靶标。我们实验室的工作假设是，罗恩受体信号传导是人类胰腺癌中侵入性生长和生存的有效启动子，代表了潜在的有价值的治疗靶点。为了支持这一想法，我们最近表明，罗恩受体下调可以使胰腺癌细胞在体内敏感到吉西他滨。最近的出版物也证明了罗恩与胰腺癌与胰腺癌的相关性，该出版物记录了它是胰腺癌中通常过表达的蛋白质，可以在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，仅罗恩过表达就可以介导胰腺癌发生，并且在致癌性KRAS的情况下，它可能会加速致癌。尽管有这些发现，但我们对罗恩受体生物学的理解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）直接检验罗恩信号传导促进胰腺内肿瘤对胰腺癌的进展，2）研究胰腺癌中胰腺癌的机制和依赖性依赖性和配体独立激活的机制，以测试一种新型的ron ronoclonalalalalalalalalalal抗体的影响，以测试胰腺癌的作用。为了识别与活化的RON信号传导和癌基因成瘾相关的生物标志物。这些研究的发现将增强我们对RON生物学的理解，从而为胰腺癌中RON定向疗法的发展和进一步测试提供信息。公共卫生相关性：胰腺癌患者成功疗法的开发要求对驱动肿瘤进展和生存的分子机制有更透彻的了解。我们的实验室最近确定，大多数胰腺癌过表达RON受体酪氨酸激酶，而RON信号传导促进了胰腺癌细胞的侵入性生长和存活。在该提案中，我们将研究罗恩如何被激活，并最终影响胰腺癌的侵入性生长，并确定可能预测对RON指导疗法反应的生物标志物。