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Juliana Portela Passos, Pablo Zoroquiain, Joao Jose Mansure, Wael Almajed, Olavo Dias, Miguel N Burnier; GnRH Expression in Uveal Melanoma as a potential therapeutic target. Invest. Ophthalmol. Vis. Sci. 2016;57(12):4115.
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© ARVO (1962-2015); The Authors (2016-present)
Gonadotropin releasing hormone receptor (GnRHR) is responsible for releasing follicle-stimulating hormone as well as luteinizing hormone from the anterior pituitary. Recent studies suggest that GnRHR is also aberrantly expressed in non-hormonal related cancers, such skin melanoma and colon cancer. Moreover, a novel drug conjugate of doxorubicin and GnRH has shown promising results in the aforementioned malignancies. The purpose of this study was to analyze the protein expression of GnRHR in uveal melanoma (UM) as a new potential therapeutic target and to analyze if a UM xenograft rabbit model may be suitable for preclinical trial studies.
The UM rabbit model in which human UM cells are injected into the suprachoroidal space has been previously described. Formalin-fixed, paraffin-embedded blocks from 20 patient eyes with UM and 10 animals with primary UM and with lung metastases were studied using immunohistochemistry. Two GnRHR antibody clones (GnRH03 and the A9E4) were tested for specificity using Western Blot analysis; anterior hypophysis was used as a positive control. Immunostaining was scored as 0 for no staining, 1 for weak, 2 for moderate, and 3 for strong, as previously described in clinical trials. A Chi-square test was used to compare staining expression between rabbit and human primary tumors.
The GnRH03 clone showed only one band on Western Blot and exhibited selective expression in gonadotropic cells of the anterior hypophysis and was used in the study. GnRHR was expressed in all tumors. In human eyes, 75% presented with diffuse expression and 25% moderate; in the animal model, 70% of the eyes presented with diffuse, 20% moderate, and 10% weak expression. In lung metastases, 54% presented with diffuse, 27% moderate, and 18% weak expression. There was no significant difference in staining expression between rabbit and human primary tumors (P=0.35), or between rabbit primary and metastases (P=0.87).
GNRHR is highly expressed in human uveal melanoma samples and is a novel, potential therapeutic target. A similar expression pattern was seen in rabbits compared to patients, suggesting that this xenograft model, which uses human cells, should be used to evaluate the efficacy of targeted therapy against GnRHR in primary and metastatic uveal melanoma.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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