Stathmin Phosphorylation as a Target for Blocking Metastasis in Prostate Cancer
Abstract
Stathmin (Stmn1) is a protein that increases in many cancers including prostate cancer and correlates with cancer progression and poor predictive outcomes. However, to develop Stathmin as an effective target for cancer therapy, it is essential to determine whether the level of Stathmin expression correlates with its cancer-promoting activity. The literature and our preliminary data provide evidence that Stathmin activity is regulated by a process called phosphorylation. Stathmin causes prostate cancer cell growth when it is phosphorylated on one amino acid (number 16), and it likely causes metastasis when it is phosphorylated on another amino acid (number 25). Therefore, it is essential to determine how Stathmin activity can be selectively manipulated by a drug to inhibit prostate cancer cell growth without increasing the risk of more aggressive metastasis. Our approach is to manipulate the expression of the key amino acids (called Serine 16, 25, 38, and 63) and determine the process by which each one of these serines regulates one of the processes involved in the development of metastatic cancer. These processes include: (1) the ability of cells to grow and form a tumor, (2) the property of migration (or movement) that allow cells to break loose from the other cells they are attached to, and (3) the property of invasion, which allows cells to leave the prostate and metastasize to other organs. We have available four drugs that will selectively prevent phosphorylation on Serines 16, 25, 38 or 63. These drugs will be tested in cell culture to determine the one that is most effective in inhibiting prostate cancer cell growth without activating a process that could cause more aggressive metastasis. Our preliminary work suggests that the small molecule inhibitor called KN-93 inhibits Serine 16 phosphorylation and could be a candidate for therapy development. KN-93 will be tested either alone, or in combination with androgen deprivation therapy, to determine how effectively it inhibits PCa cell proliferation and prevents the risk of more aggressive metastasis as compared to androgen deprivation alone. We have developed a new animal model (which uses zebrafish embryos as host animals for human prostate cancer cell grafts) for drug testing. The casper zebrafish do not have skin pigment and, therefore, they are transparent. Furthermore, their blood vessels carry a marker that causes them to glow brilliant red under a certain wavelength of light. When we label human prostate cancer cells with a dye that glows green under a different wavelength of light and inject the cells into the fish, we can visually track and film the green-glowing cells through the red-fluorescing blood vessels of the fish in living color. This model allows us to literally see when metastatic cells enter into the circulation and when they invade back into the tissue and form metastatic lesions. This model will be used to perform preclinical tests, for example, implanting the cells carrying a Stathmin mutation into the fish, treating the fish by adding the drug KN-93 with/without drugs used in the clinic for androgen deprivation (for example, abiraterone or enzalutamide) into the water that the fish are swimming in, and recording (filming) how effective the drug is in preventing/inhibiting tumor growth and preventing cells from entering the bloodstream and metastasizing to tissues/organs. In summary, contributions of this study to advancing the field of prostate cancer research include: (1) providing evidence that Stathmin is a clinically relevant target for the treatment for high grade/metastatic cancer; (2) identifying new drugs (e.g., KN-93) that could be used to specifically target Serine 16 and inhibit prostate cancer cell proliferation without increasing the risk of more aggressive metastasis; (3) providing a novel zebrafish xenograft assay for analyzing the metastatic potential of human prostate cancer cells and for drug discovery; and (
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710601
Entities
People
- Susan Kasper
Organizations
- United States Army
- University of Cincinnati