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

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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.