Grant: Project Grant

Prostate cancer grows and spreads under the influence of androgens (male steroids). For this reason, hormonal therapies are used to treat patients with metastatic disease. Unfortunately, these therapies are only transiently effective; eventually patients develop castration-resistant prostate cancer (CRPC) that continues to grow and spread. While newer anti-androgens provide some respite, CRPC cells soon develop resistance to these drugs as well. We propose a highly innovative approach for better control of CRPC that targets Gli proteins in prostate cancer cells. Gli proteins regulate genes that are needed for cancer cell growth and division. Our preliminary work has shown that androgens activate Gli proteins in prostate cancer cells and that Gli activation is required for continued growth of CRPC cells. We have also developed some novel tools that interfere with Gli activation and these agents slow CRPC cell growth significantly. The Aims of our proposed work will provide proof-of-principle that androgen-activated Gli proteins are the drivers of CRPC growth and that interference with Gli activation is a rationale strategy for better control of CRPC. Using advanced genomic analyses, we will characterize the cell growth genes that are regulated by Gli in CRPC cells. Finally, we will work with collaborators to determine the 3-dimensional structure of Gli proteins and then use a computerized docking strategy to identify new drugs that block Gli activities in CRPC cells and robustly halt their growth. We expect that our work will provide the basis for mounting a novel attack on CRPC that targets Gli proteins and provides for much better control of the disease in CRPC patients. Our work will also be relevant to other tumour systems exemplified by breast, pancreatic and lung cancer, that rely on Gli proteins for their growth.