Nuclear receptor LRH-1 in pancreatic cancer

胰腺癌中的核受体LRH-1

• 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
• 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

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，手术切除胰腺是约20%患者的早期肿瘤的唯一治疗方法，仅8%患者的最佳临床结局为2年生存。由于早期诊断是不可能的，大多数胰腺癌患者被诊断为不可手术的肿瘤，并接受化疗和放疗治疗。批准用于胰腺癌的化疗药物不是器官或组织特异性的，具有严重的副作用，并且不会导致显著的长期生存。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方面取得了重大进展。这些研究已经为开发新的癌症治疗提供了靶点，其抗癌作用将基于选择性抑制肿瘤相关调节蛋白。靶向治疗使癌细胞生存所必需的特定分子通路失效，但可能使正常细胞失效。由于正常细胞相对不受伤害，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靶点正在临床研究中，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，将探讨胰腺发育的一个重要的调节器，核受体LRH-1，在胰腺癌细胞的功能。这种蛋白质已经被证明在包括胃肠道肿瘤在内的几种类型的癌症的触发和进展中发挥关键作用。最近对LRH-1与促进许多转移性癌症的有效癌蛋白连环蛋白复合物的结构研究为发现LRH-1活性的拮抗剂提供了令人信服的论据。正如我们在这个提议中所合理化的那样，我们假设LRH-1是发现胰腺癌治疗方法的新靶点。 在这项工作中，我们建议发现抑制胰腺癌细胞中LRH-1活性的化合物。这些新的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，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，以确定新的靶点并开发新的治疗方法。我们在本授权申请中描述的综合数据表明，核受体LRH-1是发现胰腺癌治疗方法的新靶点。该提案的目的是找到抑制胰腺肿瘤中LRH-1活性的化合物。