Uveal melanoma is the most common primary intraocular tumor in adults. Although primary uveal melanoma can be effectively treated by surgery and radiotherapy, there are no therapeutic agents with proven efficacy against metastases. Uveal melanomas characteristically metastasize to the liver. As a result, liver metastasis represents the leading cause of death in uveal melanoma patients. Due to the absence of effective anti-metastatic modalities, the five year mortality rate for patients with uveal melanoma remains at 50% and thus, has changed little in the past 30 years. These grim statistics underscore the urgent need to develop and evaluate strategies for preventing the invasion and metastasis of intraocular melanomas. The long-term goal of this project is to better understand the pathophysiology of intraocular melanoma metastasis and to develop strategies to reduce the risk of metastatic disease in uveal melanoma patients. The proposed studies will consider three basic specific aims. The first specific aim will test the hypothesis that epithelioid uveal melanoma cells possess distinct biological and/or immunological characteristics that account for the greater malignant potential of uveal melanomas comprised predominantly of epithelioid cellular elements. These studies will compare epithelioid and spindle uveal melanoma cell lines for various quantitative and qualitative characteristics that could contribute tb the cells' metastatic potential in a murine model. The second specific aim will test the hypothesis that tPA activity correlates with metastatic potential of orthotopically transplanted human and murine uveal melanoma cells and that interference with tPA function will reduce the incidence and severity of spontaneous metastases. The third specific aim will test the hypothesis that spontaneous metastasis of intraocular melanomas can be inhibited by gene therapy by introducing cDNA encoding plasminogen activator inhibitors, PAI-1 and PAI-2, via replication-defective adenovirus vectors which will be inoculated directly into the eyes of mice harboring intraocular melanomas.
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