Uveal melanoma and macular degeneration : molecular biology and potential therapeutic applications

Sammanfattning: Uveal melanoma is the most common primary intraocular malignant tumor in adults with 30% to 50% of patients that ultimately succumb to metastatic disease, mainly to the liver. Although new diagnostic and therapeutic tools have been developed during the most recent years, only the eye conservation rate has been achieved, while the survival rate remains poor. Neovascular age-related macular degeneration (AMD) is a disease where abnormal blood vessels grow in the macula and cause blindness and is the leading cause for legal blindness in many industrialised countries. Angiogenesis and more specifically growth factors are thought to be responsible for the development of both tumors and neovascular AMD. The aim of the study was to identify prognostic markers for uveal melanoma and potential new therapeutic applications for both uveal melanoma and exudative AMD. Paraffin-embedded tumor specimens from 132 patients with primary uveal melanoma were analyzed with immunohistochemistry by using well-established specific antibodies against c-Met and IGF-1R. We found that the expression of both IGF-1R and c-Met was significantly associated with melanoma-specific mortality while IGF-1R showed to be a stronger prognostic marker than other currently used such as tumor cell type and tumor diameter. That could suggest a possible role of these two receptors in the spread of uveal melanoma while IGF-1R could be considered as prognostic tool and a therapeutic target. The elevated mortality rate of uveal melanoma is due to a high incidence of metastases, which occur preferentially in the liver. We showed that intraperitoneal injections of picropodophyllin (PPP), an inhibitor of IGF-1R, efficiently blocks uveal melanoma growth in vitro using different uveal melanoma cell lines and in vivo in uveal melanoma xenografts. Furthermore PPP inhibited several mechanisms involved in metastasis, including tumor cell adhesion to extracellular matrix proteins, activity and expression of matrix metalloproteinase 2, and also significantly reduced the number of the micrometastases to the liver. Oral chemotherapy generally represents a fundamental change and challenge at the same time in contemporary oncology practice. We demonstrated that oral administration of PPP completely blocks the growth of uveal melanoma xenografts and was well tolerated by the mice. PPP also reduced expression of IGF-1 dependent VEGF in uveal melanoma tumors. This effect and the anti-angiogenic response probably contribute to the high anti-tumor efficacy of PPP. PPP was also found to be superior to the other anti-tumor agents such as imatinib mesylate, cisplatin, 5-FU and doxorubicin in killing uveal melanoma cells. We could only detect a limited synergistic effect with some of them in combination with PPP. There is now compelling evidence that targeting angiogenesis in general and VEGF signaling in particular is a meaningful approach for the therapy of both cancer and exudative AMD. We could show that PPP efficiently reduces experimental CNV and inhibits the VEGF secretion from RPE cells. This thesis highlights the possibility of using IGF-1R as a prognostic marker for uveal melanoma as well as that targeting the receptor with inhibitors like PPP could offer a useful option in therapy of uveal melanoma and exudative AMD.