title: Combination therapy targeting the tumor microenvironment is effective in a model of human ocular melanoma.
abstract: BACKGROUND
  Ocular 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.
  
  
  METHODS
  Migration 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.
  
  
  RESULTS
  Lenalidomide 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.
  
  
  CONCLUSIONS
  Lenalidomide 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.
authors.affiliation: Tumor Angiogenesis Section, Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. david_mangiameli@nih.gov
authors.forename: David P
authors.initials: DP
authors.lastname: Mangiameli
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Blansfield
authors.forename: Stephan
authors.initials: S
authors.lastname: Kachala
authors.forename: Dominique
authors.initials: D
authors.lastname: Lorang
authors.forename: Peter H
authors.initials: PH
authors.lastname: Schafer
authors.forename: George W
authors.initials: GW
authors.lastname: Muller
authors.forename: David I
authors.initials: DI
authors.lastname: Stirling
authors.forename: Steven K
authors.initials: SK
authors.lastname: Libutti
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D001557:Benzenesulfonates / Q000627:therapeutic use; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005134:Eye Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D066298:In Vitro Techniques; D000077269:Lenalidomide; D008545:Melanoma / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011725:Pyridines / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077157:Sorafenib; D013792:Thalidomide / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D011725:Pyridines; D009536:Niacinamide; D013792:Thalidomide; D000077157:Sorafenib; D000077269:Lenalidomide