State University of New York at Binghamton Binghamton United States
Despite earlier detection and improved therapies, prostate cancer remains a leading cause of cancer-related death among men in the US. Castration resistant prostate cancer CRPC represents the most dangerous and presently incurable stage of the disease. In this grant, weexplore a new strategy to block the activity of a clinically relevant target known as Hedgehog proteins Hhs. Hhs comprise a family of extracellular signaling proteins that contribute to the development and progression of prostate cancer. Our strategy to inhibit Hhs as a means to suppress prostate cancer takes aim at a key biosynthetic reaction called cholesterolysis. In cholesterolysis, the oncogenic Hh polypeptide is generated through a peptide cleavage reaction involving cholesterol. Cholesterolysis represents an attractive therapeutic target because 1 the transformation is unique to Hh proteins, 2 it occurs upstream of all known oncogenic signaling events and 3 it is required for all known Hh signaling events. We are developing and applying tools to discover this new class of compounds. Our approach seeks to combine rational inhibitor design Major task 1, complementary small molecule screens Major task 2, and preclinical tests Major task 3. The patients most likely to benefit from this work are those who are suffering from or at risk of developing CDRP. In this annual report, we summarize work that toward Major task 2 and outline our plans for year 3 to reach a critical milestone identifying a tight binding, selective inhibitor of Hh cholesterolysis.