Screening for antagonists of nuclear receptor LRH-1 in pancreatic cancer cells

胰腺癌细胞核受体LRH-1拮抗剂的筛选

基本信息

批准号：
8260928
负责人：
ROBERT J FLETTERICK
金额：
$ 3.86万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-01-15 至 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8260928
关键词：
Adverse effects Affinity Animal Model Animals Antineoplastic Agents Binding Cancer Cell Growth Cell Proliferation Cells Chemicals Clinical Trials Development Diagnosis Disease Distant Drug Delivery Systems Ductal Epithelium Gene Targeting Genes Genetic Transcription Goals Homologous Gene Human Image Incidence Lead Ligands Link Liver Malignant neoplasm of pancreas Malignant neoplasm of prostate Mediating Methods Modification Neoplasm Metastasis Nuclear Receptors Organ Pancreas Pancreatic Ductal Adenocarcinoma Pharmaceutical Preparations Property Proteins RNA Research Role Scanning Screening procedure Signal Pathway Small Interfering RNA Staging Testing Therapeutic Tissues United States National Institutes of Health X-Ray Crystallography base c-myc Genes cancer cell cell growth chemotherapy cytotoxic effective therapy established cell line genetic regulatory protein genome wide association study high throughput screening inhibitor/antagonist mortality novel oncology pancreatic cancer cells pancreatic neoplasm protein expression receptor receptor binding receptor function research study small molecule small molecule libraries smoothened signaling pathway transcription factor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): The diagnosis of pancreatic cancer is devastating, with mortality nearing its incidence rates. Drugs approved for chemotherapy of pancreatic cancer are not organ or tissue specific, have severe side effects and do not result in significant long-term survival. Thus, finding specific, pancreatic tumor- associated regulatory proteins and efficient drugs targeting these proteins remains a challenging goal. A novel protein target that could be used for treatment of pancreatic cancer was identified in recent research carried out in the PI's lab. The protein is the nuclear receptor LRH-1 (Liver Receptor Homologue 1), which functions in multiple signaling pathways associated with pancreatic tumor genesis. The expression of LRH-1 protein is dramatically increased in human pancreatic ductal adenocarcinomas, with metastatic tumors showing the highest levels of the receptor. Importantly, blocking of LRH-1 by receptor specific small inhibitory RNA molecules arrests pancreatic cancer cell growth and proliferation. Unfortunately, no small molecules-inhibitors of LRH-1 are known. We propose to discover selective inhibitors of LRH-1 activity in pancreatic cancer cells and analyze their effects on cancer cell growth and spread. Our proposed study relies on the original combination of the primary, secondary and tertiary screens, as well as complementary sophisticated analyses that would allow an efficient elimination of false positive hits and identification of regulatory molecules selectively targeting LRH-1 receptor. Once discovered and characterized, the identified LRH-1 inhibitors could lead to development of novel and efficient pancreatic cancer drugs, which would advance the existing pancreatic cancer therapeutics.

描述（由申请人提供）：胰腺癌的诊断是毁灭性的，死亡率接近其发病率。批准用于胰腺癌化学疗法的药物不是器官或组织特异性的，具有严重的副作用，并且不会导致长期生存。因此，找到特定的胰腺肿瘤相关调节蛋白和针对这些蛋白质的有效药物仍然是一个挑战性的目标。在PI实验室中进行的最新研究中，发现了一种可用于治疗胰腺癌的新型蛋白质靶标。蛋白质是核受体LRH-1（肝受体同源1），该蛋白在与胰腺肿瘤起源相关的多种信号通路中起作用。在人胰腺腺癌中，LRH-1蛋白的表达显着增加，转移性肿瘤显示受体的最高水平。重要的是，受体特异性抑制性RNA分子阻止LRH-1会阻止胰腺癌细胞的生长和增殖。不幸的是，LRH-1的分子抑制剂均未知道。我们建议发现胰腺癌细胞中LRH-1活性的选择性抑制剂，并分析其对癌细胞生长和扩散的影响。我们提出的研究依赖于主要，次级和第三级筛查的原始组合以及互补的复杂分析，这些分析将有效消除假阳性命中和选择性靶向LRH-1受体的调节分子的鉴定。一旦发现并表征了鉴定的LRH-1抑制剂，可能会导致新颖有效的胰腺癌药物的发展，这将推动现有的胰腺癌治疗剂。