Cyclooxygenase-2 and other targets of adjuvant therapies for uveal melanoma

Uveal melanoma has a high mortality rate, with approximately 45% of patients dying due to liver metastasis within 15 years of initial diagnosis and local treatment. As the eye lacks lymphatics, there is no staging of uveal melanoma according to lymph node metastasis. The search for new prognostic factors and therapeutic targets is therefore crucial to the advancement of uveal melanoma research. The expression of cyclooxygenase-2 (COX-2) has been investigated in human malignancies such as cutaneous melanoma. Immunohistochemical studies were therefore used to show that uveal melanomas do express COX-2 and that this expression is associated with various histopathological markers of poor prognosis. A novel sub-classification of mixed-cell-type tumours was devised, according to COX-2 expression.The numerous studies of COX-2 expression in human malignancies have focused on COX-2 expression in tumour cells. This work shows COX-2 to be expressed in uveal melanoma tumour cells and tumour-associated macrophages (TAM), with a higher amount of COX-2 expression associated with a higher amount of TAM infiltration. These results may help explain the poor prognosis previously attributed to a high amount of TAM infiltration in uveal melanoma.This thesis also investigated the co-expression of COX-2, insulin-like growth factor 1 receptor (IGF-IR) and phosphorylated-Akt (p-Akt). A recent paper had shown IGF-1R expression to be associated with a higher risk of uveat melanoma metastasis. IGF-1R expression, present to different degrees in almost all uveal melanoma cases, represents the presence of the receptor, whereas p-Akt expression represents an activated downstream pathway. This thesis showed that p-Akt is expressed in uveal melanoma. While some uveal melanoma cases co-expressed COX-2, IGF-1R and p-Akt, all cases were positive for at least one of the three markers.Studies in human malignancies, including uveal melanoma, have shown COX-2 inhibitors to have effects on both COX-2 positive and negative tumour cells. The effects of COX-2 inhibitors on IGF-1R and p-Akt have been postulated as possible mechanisms behind these COX-2 independent effects. This work has provided a rationale for the study of COX-2 inhibitors, alone or in combination with IGF-1R inhibitors, as systemic adjuvant treatment of this life-threatening intra-ocular malignancy