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

描述(申请人提供)：美国每年有40,000多人患胰腺癌，全球范围内有60多万人罹患肝细胞癌，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)的肠道肿瘤形成中发挥了作用，这种疾病影响到7000人中的1人。这些癌症都没有直接的、特定的药物治疗，而且都有显著的发病率和死亡率。最近对它们的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Homolog-1(LRH-1)的染色体区域。这种孤立的核受体也被证明通过Wnt/-catenin和PDX-1 hedgehog途径活跃在细胞增殖中，这两个途径在肝癌和胰腺癌的肿瘤发生中起活跃作用。在FAP的小鼠模型中，LRH-1的减少被证明可以减少肿瘤负担，并且LRH-1的mRNA沉默减少了胰腺癌细胞的增殖。LRH-1在胃肠道肿瘤发病机制中的核心作用使其成为新药发现的一个有吸引力的靶点。除了肿瘤发生的新定义外，LRH-1在胃肠道、肝脏和胰腺等胃肠系统的胚胎发育以及胆汁酸和胆固醇稳态中也发挥着重要作用。了解LRH-1的功能是未来器官发生、肿瘤发生和胃肠内稳态研究的基础。这项工作建议开发和表征特异性的，非细胞毒性的LRH-1功能抑制剂，作为潜在的治疗剂和更广泛的研究工具，用于研究器官发生和肿瘤发生。这些目标将通过旨在研究细胞内抑制剂功能的新型细胞分析以及建立的LRH-1的X射线结晶学方法来实现：利用差示扫描荧光(DSF)和表面等离子体共振(SPR)技术的抑制剂复合体和抑制剂结合分析。这些结构和技术目前已在赞助商的实验室中到位，使拟议的目标立即可行。在这项建议中开发的新型LRH-1抑制剂有可能改变一些影响儿童和成人的最具破坏性的癌症的治疗方法。除了临床意义外，本研究开发的抑制剂还将为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My K08的应用开发提供基础。 公共卫生相关性：影响胃肠道系统(包括胰腺、肝脏、胃和结肠)的癌症在不同的年龄和种族中都与巨大的发病率和死亡率有关。对安全、特定药物治疗的研究将扩大家庭可用的治疗选择，并为研究这些疾病的发病机制提供宝贵的工具。

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. PUBLIC HEALTH RELEVANCE: Cancers affecting the gastrointestinal system (including pancreas, liver, stomach and colon) are associated with tremendous morbidity and mortality in a wide range of ages and ethnicities. Research into safe, specific drug-based therapy will expand treatment options available to families as well as provide valuable tools for research into the pathogenesis of these disorders.