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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37CA030276-16
Application #
2007339
Study Section
Visual Sciences C Study Section (VISC)
Project Start
1981-07-01
Project End
1999-12-31
Budget Start
1997-01-01
Budget End
1997-12-31
Support Year
16
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
City
Dallas
State
TX
Country
United States
Zip Code
75390
Han, Zhiqiang; Brown, Joseph R; Niederkorn, Jerry Y (2016) Growth and Metastasis of Intraocular Tumors in Aged Mice. Invest Ophthalmol Vis Sci 57:2366-76
Sadegh, Leila; Chen, Peter W; Brown, Joseph R et al. (2015) NKT cells act through third party bone marrow-derived cells to suppress NK cell activity in the liver and exacerbate hepatic melanoma metastases. Int J Cancer 137:1085-94
Niederkorn, Jerry Y (2013) Corneal transplantation and immune privilege. Int Rev Immunol 32:57-67
Li, Haochuan; Niederkorn, Jerry Y; Sadegh, Leila et al. (2013) Epigenetic regulation of CXCR4 expression by the ocular microenvironment. Invest Ophthalmol Vis Sci 54:234-43
Yang, Wanhua; Li, Haochuan; Mayhew, Elizabeth et al. (2011) NKT cell exacerbation of liver metastases arising from melanomas transplanted into either the eyes or spleens of mice. Invest Ophthalmol Vis Sci 52:3094-102
Li, Haochuan; Yang, Wanhua; Chen, Peter W et al. (2009) Inhibition of chemokine receptor expression on uveal melanomas by CXCR4 siRNA and its effect on uveal melanoma liver metastases. Invest Ophthalmol Vis Sci 50:5522-8
Niederkorn, Jerry Y (2009) Immune escape mechanisms of intraocular tumors. Prog Retin Eye Res 28:329-47
Yang, Wanhua; Li, Haochuan; Chen, Peter W et al. (2009) PD-L1 expression on human ocular cells and its possible role in regulating immune-mediated ocular inflammation. Invest Ophthalmol Vis Sci 50:273-80
Li, Haochuan; Alizadeh, Hassan; Niederkorn, Jerry Y (2008) Differential expression of chemokine receptors on uveal melanoma cells and their metastases. Invest Ophthalmol Vis Sci 49:636-43
Yang, Wanhua; Chen, Peter W; Li, Haochuan et al. (2008) PD-L1: PD-1 interaction contributes to the functional suppression of T-cell responses to human uveal melanoma cells in vitro. Invest Ophthalmol Vis Sci 49:2518-25

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