Uveal melanoma is an aggressive cancer of the eye. There is no cure for metastatic disease, and therefore it is always fatal. Predictive tests can identify patients with aggressive tumors but require tumor sampling which risks vision, and in small tumors is not always an option. Development of a blood-based test that can differentiate benign (non-cancerous) tumors from low grade or aggressive uveal melanoma is needed to improve survival. Our group has discovered a new tumor cell population in the blood of cancer patients, created when a tumor cell and a white blood cell fuse together. These cells, called circulating hybrid cells, can travel to distant sites, thereby spreading disease to other places in the body. In our earlier studies in pancreatic cancer patients we showed that the numbers of circulating hybrid cells can predict overall survival. Now, we have found circulating hybrid cells in the blood of patients with uveal melanoma. For this grant application, we will evaluate levels of circulating hybrid cells in patients with benign tumors called choroidal nevi and compare the levels to those in patients with uveal melanoma, where we anticipate higher numbers. We will explore whether measuring circulating hybrid cell levels may be helpful in diagnosing small uveal melanomas when the diagnosis is not clear based upon existing methods. We will also measure levels of circulating hybrid cells in uveal melanoma patients over time to see if circulating hybrid cell levels decrease after the eye tumor is treated. We predict that the numbers of circulating hybrid cells decrease over time after treatment of the eye tumor, except in patients who have already had spread of their melanoma to another site in the body. If only a small number of cells have spread, traditional imaging testing cannot detect the disease spread. If successful, measuring circulating hybrid cell levels in patients may allow us to identify the patients with disease spread earlier, when there may be better options for treating the cancer. Finally, we will determine whether we can isolate circulating hybrid cells from the blood to perform the same testing that currently requires tumor biopsies. If successful, this project will be the first step in developing a minimal-risk “liquid biopsy” for uveal melanoma. This will impact treatment decisions, allow all patients to have the benefit of the newest predictive testing, and will open the door to repeated testing over time to detect disease spread earlier and monitor responses to treatment. We will be able to study the biology of disease progression and learn more about the cells involved in uveal melanoma—an important step in finding new treatments for this deadly cancer.