Nuclear receptor LRH-1 in pancreatic cancer

胰腺癌中的核受体LRH-1

基本信息

批准号：
8050155
负责人：
ROBERT J FLETTERICK
金额：
$ 16.3万
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：
2010
资助国家：
美国
起止时间：
2010-03-23 至 2012-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8050155
关键词：
Adverse effects Affect Animal Model Antineoplastic Agents Applications Grants Binding Binding Sites Biological Assay Biosensor Cancer Cell Growth Cancer Patient Cancer cell line Cancerous Cell Line Cell Proliferation Cells Characteristics Clinical Clinical Research Complex Cyclin D1 Data Development Diagnosis Diagnostic Neoplasm Staging Disseminated Malignant Neoplasm Early Diagnosis Excision Gastrointestinal Neoplasms Goals Growth Hormones Human Image Incidence Lead Learning Left Ligands Malignant Neoplasms Malignant neoplasm of gastrointestinal tract Malignant neoplasm of pancreas Molecular Mutation Normal Cell Nuclear Receptors Oncogene Proteins Organ Outcome Pancreas Pathway interactions Patients Pharmaceutical Preparations Pharmacologic Substance Phenotype Play Primary Neoplasm Proteins Radiation therapy Research Role Screening procedure Signal Pathway Signal Transduction Site Small Interfering RNA Surface Testing Therapeutic Tissues Toxic effect Tumor stage Work X-Ray Crystallography base c-myc Genes cancer cell cancer therapy cancer type cell growth chemotherapy design genetic regulatory protein human CCNE1 protein improved inhibitor/antagonist innovation mortality novel novel therapeutics overexpression pancreatic cancer cells pancreatic neoplasm prevent public health relevance receptor research study response small molecule libraries tumor tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): The diagnosis of pancreatic cancer is devastating with mortality rates nearing its incidence rates. At present, surgical removal of the pancreas is the only treatment available for early-stage tumors in about 20% of patients, with the best clinical outcome of 2 years survival for just 8% of patients. Since early diagnosis is impossible, most pancreatic cancer patients are diagnosed with non-operable tumors and receive chemotherapy and radiotherapy treatments. Chemotherapy drugs approved for pancreatic cancer are not organ or tissue specific, have severe side effects and do not result in significant long-term survival. Thus, there is a desperate need for improved therapeutic options and effective pancreatic cancer drugs. Recent research has led to significant advances in understanding of the genetic changes and signaling pathways characteristic to pancreatic cancer. These studies already suggest targets for the development of novel cancer therapeutics whose anti-cancer effects would be based on selective inhibition of tumor-associated regulatory proteins. Targeted therapies disable specific molecular pathways that are absolutely required for survival of cancer cells but may be dispensable for normal cells. Since normal cells are left relatively unharmed, the targeted therapies would lead to less severe toxicities. Although several specific protein targets are currently in clinical studies, to date, there are no effective targeted anti pancreatic cancer therapeutics. We propose experiments that will explore function of an essential regulator of pancreatic development, the nuclear receptor LRH-1, in pancreatic cancer cells. This protein is already shown to play a critical role in triggering and progression of several types of cancers including gastrointestinal tumors. Recent structural studies of LRH-1 in complex with the potent oncoprotein, catenin, which promotes many metastatic cancers, make a compelling argument for discovery of antagonists of LRH-1 activity. As we rationalize in this proposal, we hypothesize that LRH-1 is a novel target for the discovery of pancreatic cancer therapeutics. In this work, we propose to discover compounds that inhibit the LRH-1 activity in pancreatic cancer cells. These novel regulatory compounds could be developed into a pharmaceutical that will inhibit proliferation of cancer cells in pancreatic tumors, advancing the existing pancreatic cancer therapies. PUBLIC HEALTH RELEVANCE: Determination of mechanisms that trigger and drive pancreatic cancer growth is urgently needed to pinpoint new targets and to develop novel therapeutics. The combined data that we describe in this grant application suggest that nuclear receptor LRH-1 is a novel target for the discovery of pancreatic cancer therapeutics. The aim of this proposal is to find compounds that inhibit the LRH-1 activity in pancreatic tumors.

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。目前，胰腺的外科手术去除是大约20％的患者的唯一可用于早期肿瘤的治疗方法，仅8％的患者生存2年的临床结果最佳。由于早期诊断是不可能的，因此大多数胰腺癌患者被诊断出患有不可忍受的肿瘤并接受化疗和放疗治疗。批准用于胰腺癌的化学疗法药物不是器官或组织特异性的，具有严重的副作用，不会导致长期生存。因此，迫切需要改善治疗选择和有效的胰腺癌药物。最近的研究导致了了解胰腺癌特征的遗传变化和信号传导途径的重大进展。这些研究已经提出了开发新型癌症治疗剂的靶标，其抗癌作用将基于对肿瘤相关的调节蛋白的选择性抑制。靶向疗法禁用癌细胞存活绝对需要的特定分子途径，但对于正常细胞可能是可分配的。由于正常细胞相对不受伤害，因此靶向疗法会导致严重的毒性。尽管目前在临床研究中有几个特定的蛋白质靶标，但迄今为止，尚无有效的靶向抗胰腺癌治疗剂。我们提出的实验将探索胰腺癌细胞中胰腺发育基本调节剂核受体LRH-1的功能。该蛋白已经显示出在触发和进展（包括胃肠道肿瘤）的几种类型的癌症中起关键作用。 LRH-1与有效的癌蛋白Catenin促进了许多转移性癌症的最新结构研究，这是发现LRH-1活性拮抗剂的令人信服的论点。当我们在该提案中合理化时，我们假设LRH-1是发现胰腺癌治疗剂的新目标。在这项工作中，我们建议发现抑制胰腺癌细胞LRH-1活性的化合物。这些新型的调节化合物可以发展为一种药物，该药物将抑制胰腺肿瘤中癌细胞的增殖，从而推进现有的胰腺癌疗法。公共卫生相关性：迫切需要确定触发和推动胰腺癌生长的机制，以确定新的靶标和开发新的治疗剂。我们在此赠款应用中描述的组合数据表明，核受体LRH-1是发现胰腺癌治疗剂的新目标。该提案的目的是找到抑制胰腺肿瘤LRH-1活性的化合物。