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

描述（由申请人提供）：胰腺癌每年在美国影响超过40，000人，全世界肝细胞癌（HCC）影响超过600，000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）中发现的肠道肿瘤发生中发挥作用，FAP是一种影响高达1/7000个体的疾病。这些癌症中没有一种有针对性的特定药物治疗，并且都具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确定了8个SNP，其中5个定位于肝受体同源物-1（LRH-1）的染色体区域。这种孤儿核受体也已被证明通过Wnt/β-连环蛋白和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。已经显示LRH-1的减少减少FAP小鼠模型中的肿瘤负荷，并且LRH-1的mRNA沉默减少胰腺癌细胞增殖。LRH-1在胃肠癌发病机制中的核心作用使其成为新药发现的有吸引力的靶点。除了新定义的肿瘤发生作用外，LRH-1在胃肠道系统（包括肠道、肝脏和胰腺）的胚胎发育中具有关键作用，并且在胆汁酸和胆固醇稳态中具有重要作用。了解LRH-1的功能是未来器官发生、肿瘤发生和胃肠道内环境稳定研究的基础。这项工作提议开发和表征LRH-1功能的特异性、非细胞毒性抑制剂，既可用作潜在的治疗剂，也可更广泛地用作器官发生和肿瘤发生研究的研究工具。这些目标将通过旨在研究细胞环境中抑制剂功能的新型基于细胞的测定以及已建立的LRH-1的X射线晶体学方法来实现：抑制剂复合物和利用差示扫描荧光法（DSF）和表面等离子体共振（SPR）技术的抑制剂结合测定。这些结构和技术目前已在申办者的实验室中就位，使拟议的目标立即可行。该提案中开发的新型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管理。除了临床意义外，本研究中开发的抑制剂将为细胞和动物模型中LRH-1介导的发育和发病机制的基础科学研究提供工具，并为K 08应用的开发提供基础。 公共卫生相关性：影响胃肠道系统（包括胰腺、肝脏、胃和结肠）的癌症在广泛的年龄和种族中与巨大的发病率和死亡率相关。对安全、特异性药物治疗的研究将扩大家庭的治疗选择，并为研究这些疾病的发病机制提供有价值的工具。

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.