Inhibition of Pancreatic Cancer Cell Proliferation by LRH-1 Inhibitors.

摘要

We propose to find selective and potent compounds that inhibit activity of the nuclear receptor LRH-1 (Liver Receptor Homolog 1) in human pancreatic cancer cells, blunting their growth, proliferation and spread. Our research is innovative in its approach because the target protein is known to control not just one but multiple regulatory mechanisms essential for tumor growth and spread. Thus by targeting this protein, one might be able to de-activate these mechanisms, inhibiting and even reversing the progression of pancreatic cancer. Conceivably, dietary modifications that affect LRH-1 function may spawn a prophylactic approach to the disease. An additional appeal of LRH-1 as a drug target includes its well-studied ligand-binding pocket, which could be targeted by specific drugs, and the proven efficiency of nuclear receptor inhibitors for treatment of different types of malignancies, including breast and prostate cancers. In this project, we show how to discover selective inhibitors of LRH-1 and analyze them in pancreatic cancer cells. The identified novel inhibitors of LRH-1 could then be developed into a pharmaceutical that will inhibit growth and proliferation of cancer cells in pancreatic tumors, advancing the existing pancreatic cancer therapies.