LRH-1: Structure-based Approach to Drug Design for Gastrointestinal Tumors

描述（由申请人提供）：胰腺癌每年影响美国4万多人，全球肝细胞癌（HCC）影响超过60万人，使其成为癌症死亡的第三大原因。最近的证据表明，LRH-1在家族性腺瘤性息肉病（FAP）的肠道肿瘤发生中发挥作用，这种疾病的发病率高达1 / 7000。这些癌症都没有直接的、特定的医学治疗方法，而且都有很高的发病率和死亡率。最近对其发病机制有了新的认识：一项全基因组关联研究发现了8个snp，其中5个定位于肝脏受体同源物-1 （LRH-1）的染色体区域。这种孤儿核受体也被证明通过Wnt/ -catenin和PDX-1 hedgehog途径在细胞增殖中具有活性，这些途径在HCC和胰腺癌的肿瘤发生中具有活性。在FAP小鼠模型中，LRH-1的减少已被证明可以减轻肿瘤负荷，而LRH-1 mRNA的沉默可减少胰腺癌细胞的增殖。LRH-1在胃肠癌发病机制中的核心作用使其成为新药开发的一个有吸引力的靶点。除了新定义的肿瘤发生作用外，LRH-1在包括肠道、肝脏和胰腺在内的胃肠道系统的胚胎发育中起关键作用，并在胆汁酸和胆固醇稳态中起重要作用。了解LRH-1的功能是未来器官发生、肿瘤发生和胃肠道稳态研究的基础。这项工作提出了开发和表征特异性的、LRH-1功能的非细胞毒性抑制剂，作为潜在的治疗剂和更广泛的研究工具，用于器官发生和肿瘤发生的研究。这些目标将通过新的基于细胞的分析来实现，这些分析旨在研究细胞背景下抑制剂的功能，并建立LRH-1的x射线晶体学方法：利用差示扫描荧光法（DSF）和表面等离子体共振（SPR）技术进行抑制剂复合物和抑制剂结合分析。这些结构和技术目前已经在发起人的实验室中到位，使所提出的目标立即可行。在本提案中开发的新型LRH-1抑制剂有可能改变影响儿童和成人的一些最具破坏性的癌症的管理。除了临床意义外，本研究开发的抑制剂将为LRH-1介导的细胞和动物模型的发育和发病机制的基础科学研究提供工具，并为我的K08应用的开发提供基础。

DESCRIPTION (provided by applicant): Pancreatic cancer affects over 40,000 people in the United States each year and worldwide hepatocellular carcinoma (HCC) affects over 600,000 individuals, making it the third leading cause of cancer deaths. Recent evidence points to a role for LRH-1 in intestinal tumorigenesis found in Familial Adenomatous Polyposis (FAP), a condition affecting up to 1 in 7000 individuals. None of these cancers have directed, specific medical therapies, and all carry significant morbidity and mortality. New insight has recently been gained into their pathogenesis: a genome-wide association study identified eight SNPs, five of which localized to the chromosomal region of Liver Receptor Homolog-1 (LRH-1). This orphan nuclear receptor has also been shown to be active in cell proliferation via the Wnt/ -catenin and PDX-1 hedgehog pathways, which are active in the tumorigenesis of HCC and pancreatic cancer. Reduction of LRH-1 has been shown to reduce tumor burden in mouse models of FAP, and mRNA silencing of LRH-1 reduces pancreatic cancer cell proliferation. The central role of LRH-1 in gastroenterological cancer pathogenesis makes it an attractive target for novel drug discovery. Apart from the newly defined role of tumorigenesis, LRH-1 has critical roles in the embryological development of the gastrointestinal system including gut, liver, and pancreas as well as important roles in bile acid and cholesterol homeostasis. Understanding of LRH-1 function is fundamental to future research in organogenesis, tumorigenesis, and gastrointestinal homeostasis. This work proposes to develop and characterize specific, non-cytotoxic inhibitors of LRH-1 function for use as both potential therapeutic agents and more broadly as research tools for the study of organogenesis and tumorigenesis. These Aims will be accomplished via novel cell-based assays designed to investigate inhibitor function within a cellular context as well as established methods of X-ray crystallography of LRH-1: inhibitor complexes and inhibitor binding assays utilizing Differential Scanning Fluorimetry (DSF) and surface Plasmon resonance (SPR) technology. The constructs and techniques are currently in place in the sponsor's laboratory, making the proposed Aims immediately feasible. Novel LRH-1 inhibitors developed in this proposal have the potential to transform the management of some of the most devastating cancers affecting children and adults alike. In addition to the clinical implications, the inhibitors developed in this study will provide tools for basic science research f LRH-1 mediated development and pathogenesis in cell and animal models and provide a basis for development of my K08 application.