# Diabetic Retinopathy and Ocular Melanoma: How Far We Are?
## 4 Uveal Melanoma, Angiogenesis and Anti-Angiogenic Therapy
It may be useful to study the combination of inhibition of MEK with other agents targeting different signalling cascades (e.g., via phosphatidylinositol3 kinase). Co-inhibition of BRAF and MEK may also be useful, as BRAF inhibitors promote paradoxical activation  
Figure 3: Signalling pathways and interactions between cells in uveal melanoma proliferation. EC, endothelial cells; M, macrophages; L1 T-cells; L2 tumour infiltrating lymphocytes; NK natural killers; red lines inhibition pathways; black lines stimulation pathways. in normal tissues, thereby reducing the toxic effects of MEK inhibition. Thus, it will be more effective to inhibit the MAPK pathway in tumours, achieving a better clinical response [214]. Selumetinib (MEK1 and MEK2 inhibitor) was also studied and compared to chemotherapy and showed better progression-free survival and tumour response in patients with advanced uveal melanoma. It is known that in almost all cases of metastatic uveal melanoma (about 95%), patients have mutations in G proteins, which are responsible for activating most signalling pathways (e.g., MAPK, AKT and PKC). In vitro cellular studies revealed that selumetinib blocked the MEK pathway and inhibited uveal melanoma cell proliferation. As [PERSON] commented, targeted therapy is a promising option in uveal melanoma. So far, no systemic treatment has been successful in the treatment of this disease. Several studies are currently under development. SUMIT (NCT01974752) is a phase 3 study of selumetinib in combination with dacarbazine versus chemotherapy, where previous preclinical data reveal that the effectiveness of MEK inhibition is enhanced with inhibition of AKT or PKC. A study with tranetinib or in combination with GSK2141795, as well as a study of MEK162 and AEB071, is also under development. In this way, a MEK inhibitor may alter the response of a tumour and may be a promising therapeutic approach in uveal melanoma [218]. To date, anti-angiogenic drugs for the clinical treatment of uveal melanoma and its metastases are not available on the market yet. Currently, the primary tumour therapy is based on enucleation, local resection and radiotherapy (e.g., iodine or ruthenium brachytherapy, stereotactic and proton beam irradiation) [40]. Radiotherapy is considered the most effective treatment because it can almost completely dominate the tumour (about 97%) in all treated eyes [219; 220]. Therefore, other anti-angiogenic drugs are in demand. It is not always possible to radiate all tumours. Irradiation is known to involve a tumour with a height greater than 10.0 mm and a diameter greater than 16.0 mm. In some cases, ultrasonography does not allow the tumour to be clearly defined as it may be diffuse or multifocal, and even when neovascularization or secondary glaucoma occurs, or in the case of extracleral extension, it is not possible to use irradiation as a treatment [221; 222]. In addition, radiotherapy also has contraindications. Radiation retinopathy may occur, which is characterized by retinal ischemia, neovascularization and vessel leakage, resulting in decreased visual acuity [40]. Thus, about half of uveal melanoma patients are known to progress to metastatic disease and there is currently no effective treatment, and life expectancy in these cases is two to six months since chemotherapy and resection do not allow complete treatment but only prolong survival for a few months. Some antiangiogenic agents are being used clinically as a treatment and bring new hope for this type of tumour [40]. Table 1 summarizes some anti-angiogenic agents and their effect on tumour growth and metastases in the ocular melanoma.