Nuclear receptor LRH-1 in pancreatic cancer

描述(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，对于约20%的早期肿瘤患者，手术切除胰腺是唯一可用的治疗方法，仅有8%的患者获得了2年生存的最佳临床结果。由于早期诊断是不可能的，大多数胰腺癌患者被诊断为不能手术的肿瘤，并接受化疗和放射治疗。批准用于胰腺癌的化疗药物不是器官或组织特异性的，有严重的副作用，不会导致显著的长期生存。因此，迫切需要改进的治疗方案和有效的胰腺癌药物。最近的研究在了解胰腺癌的基因变化和信号通路方面取得了重大进展。这些研究已经提出了开发新的癌症疗法的目标，其抗癌效果将基于对肿瘤相关调节蛋白的选择性抑制。靶向治疗使特定的分子通路失效，这些通路对于癌细胞的生存是绝对必要的，但对正常细胞可能是可有可无的。由于正常细胞相对没有受到伤害，靶向治疗将导致不那么严重的毒性。尽管目前有几个特定的蛋白质靶点正在进行临床研究，但到目前为止，还没有有效的靶向抗胰腺癌疗法。我们提出的实验将探索胰腺发育的关键调节因子-核受体LRH-1在胰腺癌细胞中的功能。这种蛋白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发展中发挥关键作用。最近对LRH-1与强大的癌蛋白连环蛋白的复合体的结构研究，为发现LRH-1活性的拮抗剂提供了一个令人信服的论据。当我们在这项提议中合理化时，我们假设LRH-1是发现胰腺癌治疗的新靶点。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。这些新的调节性化合物可以被开发成一种药物，可以抑制胰腺肿瘤中癌细胞的增殖，促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推动胰腺癌生长的机制，以确定新的靶点和开发新的治疗方法。我们在这项拨款申请中描述的综合数据表明，核受体LRH-1是发现胰腺癌治疗药物的新靶点。这项提议的目的是寻找在胰腺肿瘤中抑制LRH-1活性的化合物。

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.