Grant: Project Grant

Half of prostate cancers have a common genetic abnormality, called TMPRSS2-ERG, which allows prostate cells to produce ERG in response to male sex hormone, testosterone. ERG is not normally made by prostate cells, but is known to be involved in cell movement during development. ERG also enables prostate cancer cells to migrate away from the prostate gland. This type of migration, called metastasis, is the primary cause of prostate cancer mortality. There are no therapies that target ERG. We have identified chemicals that directly bind to, and block the function of, ERG. We have also created ERG-prostate cancer models, including models from patient tumors, and have identified specific cellular changes that correlate with the ability of ERG to promote metastasis. In this application, we propose to refine the structure of our ERG-targeting chemicals for drug development and use these chemicals to study the specific events that ERG promotes to cause prostate tumor cells to metastasize. We will design new derivatives of our ERG-targeted inhibitors using computerized modelling and chemical techniques to enhance potency, solubility and stability. We will determine how these ERG-targeted chemicals affect gene expression of cancer cells and define how they impact the ability of ERG to partner with other factors in a cell. We will determine how these chemicals affect cancer cell survival, response to other stresses, and their ability to migrate and invade surrounding areas using tissue culture and animal models of prostate cancer. This project addresses a major unmet opportunity for new prostate cancer therapies by developing anti-ERG drugs that can be translated into clinical studies to benefit those 50% of prostate cancer patients whose cancers harbor these TMPRSS2-ERG genetic abnormalities.