Abstract
BackgroundOcular melanoma is the leading intraocular malignancy. There is no effective treatment for metastatic ocular melanoma. We sought a treatment targeting the tumor microenvironment as well as the tumor cells.MethodsMigration of HUVEC cells, the ability of HUVEC cells to form tubes, and proliferative capacity of a human ocular melanoma cell line were tested in the presence of lenalidomide and sorafenib alone and in combination. The compounds were also tested in a rat aortic ring assay and were tested in a highly aggressive human ocular melanoma xenograft model.ResultsLenalidomide and Sorafenib inhibit HUVEC ability to migrate and form tubes and when used in combination the inhibition is increased. The agents alone and in combination inhibit outgrowth in the rat aortic ring model. The combination of the agents improved the inhibition over either single agent. In a xenograft model, combination therapy inhibited tumor growth over inhibition by single agent alone in a significant fashion (p < 0.004: lenalidomide and p < 0.0035: sorafenib). Furthermore, spontaneous lung metastasis development was completely inhibited in the combination treated animals. Sixty percent of vehicle treated animals developed lung metastases compared to 50% of lenalidomide treated animals, and 33% of sorafenib treated animals.ConclusionLenalidomide and sorafenib are effective at targeting endothelial cells, inhibiting growth of ocular melanoma cells and can inhibit growth of tumors in a xenograft model as well as inhibit development of metastases. Combining these agents works in an additive to synergistic way to inhibit the growth of tumors and development of metastases.
Highlights
Ocular melanoma is the leading intraocular malignancy
Oxaliplatin was used as a positive control in these experiments due to its known inhibition of ocular melanoma cells in vitro and fumagillin was used as a positive control secondary to its known inhibition of endothelial cells in vitro
We used the migration assay with human umbilical vein endothelial cells (HUVEC), to see if endothelial cells sustained a functional deficit in motility when subject to lenalidomide
Summary
Ocular melanoma is the leading intraocular malignancy. There is no effective treatment for metastatic ocular melanoma. Ocular melanoma (OM) is a relatively rare diagnosis, it is the leading intraocular malignancy and accounts for approximately 5% of all melanomas It has a slight male predominance and the age-specific incidence peaks at 70 years of age[1]. OM is known for its metastatic tropism to the liver (89%), it can be found in a number of other locations, including lung (29%), bone (17%), skin or subcutaneous tissue (12%), lymph node (11%), brain (5%), and other tissues (> 20%)[2]. These sites of disease are not mutually exclusive and they underscore OM's behavior as a systemic disease. Our approach is to target the tumor microenvironment using agents which have a broad spectrum activity of against the tumor and its vasculature
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