High Throughput Screening for SCAP Inhibitors as Pancreas Cancer Therapeutics

项目总结

PROJECT SUMMARY Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of death due to cancer in the United States and will become the 2nd leading cause of cancer-related death by 2030. PDAC is typically diagnosed late in the disease process when therapeutic options are severely limited, resulting in an overall survival time of <12 months post-diagnosis and a 5-year survival rate of <10%. Therefore, new drugs that prevent PDAC primary and metastatic tumor growth are desperately needed. PDAC tumor cells are extremely proliferative and thus have a high requisite demand for membrane lipids. However, the PDAC tumor microenvironment is poorly vascularized, leading to hypoxia and limited nutrient supply. Lipid synthesis is highly oxygen-consumptive, so neoplastic cells in a hypoxic environment are challenged with meeting the demand for lipids. The sterol regulatory element-binding protein (SREBP) transcription factors maintain cellular lipid supply by increasing synthesis and uptake of cholesterol, fatty acids, and triglycerides. SREBPs are activated when lipid supply is low, and SREBP cleavage activating protein (SCAP) is required for pathway activity. Thus, tumors should require SCAP to adapt to nutrient- limiting conditions and supply lipid for membrane construction. To date, the SREBP pathway has been implicated in the growth and progression of several cancers, including colon, prostate, breast, and glioblastoma. However, the role of the SREBPs in PDAC has not been examined. Using multiple human PDAC cell lines and mouse tumor models, we demonstrated that SCAP is required for PDAC tumor development and growth, making SCAP a novel target for therapeutics. Despite the established requirement for the SREBP pathway in multiple cancers, no potent chemical inhibitor exists. To identify new candidate therapeutics, we developed a robust high throughput assay for SCAP inhibitors. Here, we build on our preliminary studies to identify potent SCAP chemical inhibitors for the treatment of pancreas cancer. AIM 1. To identify candidate SCAP inhibitors by high throughput screening. AIM 2. To validate SCAP inhibitors and conduct preliminary SAR studies. The overall goal of these studies is to identify a series of potent, chemically tractable, validated compounds that inhibit SCAP in at least two orthogonal assays with a dose-response over 100-fold concentration range. Traditional approaches to target lipid metabolism in cancer have focused on inhibition of a single enzyme required for cholesterol, isoprenoid or fatty acid synthesis. SREBPs directly regulate more than 30 genes of lipid metabolism. Thus, inhibiting SCAP will coordinately block multiple synthesis and uptake pathways and represents a novel approach to targeting lipid metabolism in cancer.