Nuclear receptor LRH-1 in pancreatic cancer

胰腺癌中的核受体LRH-1

基本信息

批准号：
7896139
负责人：
ROBERT J FLETTERICK
金额：
$ 20.16万
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/7896139
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 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，手术切除胰腺是治疗约 20% 患者早期肿瘤的唯一治疗方法，只有 8% 的患者获得 2 年生存的最佳临床结果。由于无法进行早期诊断，大多数胰腺癌患者被诊断为无法手术的肿瘤并接受化疗和放疗。批准用于胰腺癌的化疗药物不具有器官或组织特异性，具有严重的副作用，并且不会导致显着的长期生存。因此，迫切需要改进的治疗选择和有效的胰腺癌药物。最近的研究在了解胰腺癌的遗传变化和信号通路特征方面取得了重大进展。这些研究已经提出了开发新型癌症疗法的目标，其抗癌作用将基于选择性抑制肿瘤相关调节蛋白。靶向治疗使特定的分子途径失效，这些途径对于癌细胞的生存是绝对必需的，但对于正常细胞来说可能是可有可无的。由于正常细胞相对不受伤害，因此靶向治疗将导致不太严重的毒性。尽管目前有几种特定的蛋白质靶点正处于临床研究中，但迄今为止，还没有有效的靶向抗胰腺癌治疗方法。我们提出的实验将探索胰腺发育的重要调节因子核受体 LRH-1 在胰腺癌细胞中的功能。这种蛋白质已被证明在包括胃肠道肿瘤在内的多种癌症的引发和进展中发挥着关键作用。最近对 LRH-1 与强效癌蛋白连环蛋白（可促进许多转移性癌症）复合的结构研究，为发现 LRH-1 活性拮抗剂提供了令人信服的论据。当我们在这个提议中合理化时，我们假设 LRH-1 是发现胰腺癌疗法的新靶点。在这项工作中，我们打算发现抑制胰腺癌细胞中 LRH-1 活性的化合物。这些新型调节化合物可以开发成一种药物，抑制胰腺肿瘤中癌细胞的增殖，从而推进现有的胰腺癌治疗。公共卫生相关性：迫切需要确定触发和驱动胰腺癌生长的机制，以查明新靶点并开发新疗法。我们在本次拨款申请中描述的综合数据表明，核受体 LRH-1 是发现胰腺癌疗法的新靶点。该提案的目的是寻找抑制胰腺肿瘤中 LRH-1 活性的化合物。