RON Receptor in Pancreatic Cancer Biology and Therapy

胰腺癌生物学和治疗中的 RON 受体

• 批准号: 8699025
• 负责人: ANDREW M LOWY
• 金额: $ 27.53万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 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/8699025
• 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

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）：胰腺癌患者持续的令人沮丧的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。我们的研究小组和其他研究人员将罗恩酪氨酸激酶受体鉴定为胰腺癌中的过表达蛋白和潜在的新治疗靶点。我们实验室的工作假设是，罗恩受体信号传导是人胰腺癌侵袭性生长和存活的有效促进剂，代表了潜在的有价值的治疗靶点。为了支持这一观点，我们最近发现罗恩受体下调可以使胰腺癌细胞对吉西他滨在体内敏感。最近的出版物也证实了罗恩与胰腺癌的相关性，这些出版物将其记录为胰腺癌中常见的过表达蛋白，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，罗恩过表达可以单独介导胰腺癌的发生，并且在致癌Kras的情况下，它可能加速癌的发生。尽管有这些发现，我们对罗恩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。此应用程序的目标是; 1）直接检验罗恩信号传导促进胰腺上皮内瘤形成进展为胰腺癌的假设，2）研究胰腺癌中罗恩配体依赖性和配体非依赖性活化的机制，3）测试新型罗恩单克隆抗体对患者的原位生长的影响，衍生的胰腺癌异种移植物，以鉴定与活化的罗恩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罗恩生物学的理解，从而为胰腺癌RON导向疗法的开发和进一步测试提供信息。