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

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。批准用于胰腺癌化疗的药物不是器官或组织特异性的，具有严重的副作用，并且不会导致显著的长期生存。因此，寻找特异性的胰腺肿瘤相关调节蛋白和靶向这些蛋白的有效药物仍然是一个具有挑战性的目标。 在PI实验室最近进行的研究中发现了一种可用于治疗胰腺癌的新型蛋白质靶点。这种蛋白质是核受体LRH-1（肝脏受体同源物1），它在与胰腺肿瘤发生相关的多种信号通路中发挥作用。LRH-1蛋白的表达在人胰腺导管腺癌中显著增加，其中转移性肿瘤显示出最高水平的受体。重要的是，通过受体特异性小抑制RNA分子阻断LRH-1可以阻止胰腺癌细胞的生长和增殖。 不幸的是，没有已知的LRH-1的小分子抑制剂。我们建议在胰腺癌细胞中发现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初级，二级和三级筛选的原始组合，以及互补的复杂分析，这将允许有效消除假阳性命中和识别选择性靶向LRH-1受体的调节分子。一旦被发现和鉴定，所鉴定的LRH-1抑制剂可能导致开发新的和有效的胰腺癌药物，这将推进现有的胰腺癌治疗方法。

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.