Targeting Kinases in Prostate Cancer

Like all cancers, prostate cancer begins with a single cell that accumulates changes in its DNA that permanently alter the cell leading it to acquire malignant properties. One of the earliest changes results in reduction of a protein, NKX3.1, that controls cell growth and differentiation. Prostate cancer incidence increases markedly with age. Changes in the tissue of the aging prostate are believed to accelerate the cancer process. One of these changes is the appearance of inflammatory cells that attack the normal prostate cells. The inflammatory cells cause reduced levels of NKX3.1 in the prostate cells. Thus, an important control protein for cell growth and differentiation is reduced by inflammation. The process by which inflammation reduces NKX3.1 protein involves activation of a kinase in the cell that triggers degradation of the NKX3.1 protein. Kinases are the class of proteins that have been effectively blocked by the new 'targeted' anticancer treatments such as imatinib in leukemia and trastuzumab in breast cancer. We have also found that kinases are responsible for the turnover of the NKX3.1 protein in cells that is part of the routine maintenance of cellular events. Our work has shown that kinases, which are enzymes, control levels of NKX3.1 in cells. This implies that inhibiting these kinases with drugs may be an important therapeutic strategy for prostate cancer. This project will identify the kinases that are responsible for controlling cellular levels of NKX3.1. The identification of these kinases, out of nearly 600 possible candidates, will allow us to find the right drugs to interfere with their activity and thereby increase cellular levels of the tumor suppressor NKX3.1 protein.