Molecular Insights and Emerging Strategies for Treatment of Metastatic Uveal Melanoma

Abstract

Uveal melanoma (UM) is the most common intraocular cancer. In recent decades, major advances have been achieved in the diagnosis and prognosis of UM allowing for tailored treatments. However, nearly 50% of patients still develop metastatic disease with survival rates of less than 1 year. There is currently no standard of adjuvant and metastatic treatment in UM, and available therapies are ineffective resulting from cutaneous melanoma protocols. Advances and novel treatment options including liver-directed therapies, immunotherapy, and targeted-therapy have been investigated in UM-dedicated clinical trials on single compounds or combinational therapies, with promising results. Therapies aimed at prolonging or targeting metastatic tumor dormancy provided encouraging results in other cancers, and need to be explored in UM. In this review, the latest progress in the diagnosis, prognosis, and treatment of UM in adjuvant and metastatic settings are discussed. In addition, novel insights into tumor genetics, biology and immunology, and the mechanisms underlying metastatic dormancy are discussed. As evident from the numerous studies discussed in this review, the increasing knowledge of this disease and the promising results from testing of novel individualized therapies could offer future perspectives for translating in clinical use.

Electrochemotherapy with Bleomycin Enhances Radiosensitivity of Uveal Melanomas: First In Vitro Results in 3D Cultures of Primary Uveal Melanoma Cell Lines

“…The aim of therapy is to conserve the eye with useful vision as well as to minimize the risk of metastasis [ 3 , 5 ]. A disseminated UM can be treated with adjuvant immunotherapy, chemotherapy and molecular targeted therapy [ 8 ].…”

Genetic Landscape and Emerging Therapies in Uveal Melanoma

“…BAP1 encodes a deubiquinating enzyme (nuclear ubiquitin carboxy-terminal hydrolase) and is a known tumor suppressor gene. Inactivation of BAP1 has been observed in 47% of primary UM and 91% of metastatic UM, correlating with the understanding that loss of BAP1 is a key event to metastasis [ 36 , 47 ]. Deletion of chromosome 3 also usually accompanies the development of the class 2 gene expression signature, suggesting that one or more genes on chromosome 3 may regulate the emergence of a cancer stem-like phenotype [ 46 ].…”

Uveal melanoma diagnosis and current treatment options (Review)

“…In regards to hepatic metastasis, liver-directed therapies, including intra-arterial chemotherapy with fotemustine, transarterial liver chemoembolization, and isolated hepatic perfusion have shown, besides their significant theoretical advantages, encouraging results in different studies (85)(86)(87)(88)(89). Different surgical laparoscopic excisions (alone or combined with radiofrequency ablation), liver radioembolization (using yttrium-90 microspheres), and liver thermotherapy have also shown promising results and are under evaluation (90)(91)(92)(93).…”