Screening for antagonists of nuclear receptor LRH-1 in pancreatic cancer cells

University Of California, San Francisco, San Francisco CA

Investigators

Abstract

DESCRIPTION (provided by applicant): The diagnosis of pancreatic cancer is devastating, with mortality nearing its incidence rates. Drugs approved for chemotherapy of pancreatic cancer are not organ or tissue specific, have severe side effects and do not result in significant long-term survival. Thus, finding specific, pancreatic tumor- associated regulatory proteins and efficient drugs targeting these proteins remains a challenging goal. A novel protein target that could be used for treatment of pancreatic cancer was identified in recent research carried out in the PI's lab. The protein is the nuclear receptor LRH-1 (Liver Receptor Homologue 1), which functions in multiple signaling pathways associated with pancreatic tumor genesis. The expression of LRH-1 protein is dramatically increased in human pancreatic ductal adenocarcinomas, with metastatic tumors showing the highest levels of the receptor. Importantly, blocking of LRH-1 by receptor specific small inhibitory RNA molecules arrests pancreatic cancer cell growth and proliferation. Unfortunately, no small molecules-inhibitors of LRH-1 are known. We propose to discover selective inhibitors of LRH-1 activity in pancreatic cancer cells and analyze their effects on cancer cell growth and spread. Our proposed study relies on the original combination of the primary, secondary and tertiary screens, as well as complementary sophisticated analyses that would allow an efficient elimination of false positive hits and identification of regulatory molecules selectively targeting LRH-1 receptor. Once discovered and characterized, the identified LRH-1 inhibitors could lead to development of novel and efficient pancreatic cancer drugs, which would advance the existing pancreatic cancer therapeutics.