Development of new therapeutic options for the treatment of uveal melanoma

Abstract

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. Important cytogenetic and genetic risk factors for the development of UM include chromosome 3 monosomy, mutations in the guanine nucleotide-binding proteins GNAQ/GNA11, and loss of the BRACA1-associated protein 1 (BAP 1). Most primary UMs are treated conservatively with radiotherapy, but enucleation is necessary for large tumours. Despite the effectiveness of local control, up to 50% of UM patients develop metastasis for which there are no effective therapies.Attempts to utilize the targeted therapies that have been developed for the treatment of other cancers, including a range of signal transduction pathway inhibitors, have rarely produced significant outcomes in UM. Similarly, the application of immunotherapies that are effective in cutaneous melanoma to treat UM have also been disappointing. Other approaches that have been initiated involve proteasomal inhibitors and histone deacetylase inhibitors that are approved for the treatment of other cancers. Nevertheless, there have been occasional positive outcomes from these treatments in UM. Moreover, combination approaches in UM have also yielded some positive developments. It would be valuable to identify how to apply such therapies efficiently in UM, potentially via individualized tumour profiling. It would also be important to characterize UM tumours to differentiate the potential drivers of progression from those in other types of cancers.The recent identification of novel kinases and metastatic genes in UM tumours makes the development of new UM-specific treatments feasible. Accepted ArticleThis article is protected by copyright. All rights reserved A) Uveal Melanoma: Background and risk factors Uveal melanoma (UM) is the most common primary intraocular malignancy in adults and represents ~5 % of melanoma diagnoses in the US annually [1-3]. UM originates from ocular melanocytes with 85% of cases arising from the choroid region and the remainder from the ciliary body and iris [4]. The prognosis in UM is poor, in particular because around 50% of patients develop metastatic disease. Hepatic metastases occur in up to 90% of individuals, followed by metastases in lung and bones, and after establishment of metastatic disease the median survival time is only 4-5 months [5]. At the time of diagnosis, systemic metastases are reported in only 3%of patients, but it is likely that micro-metastases have already developed in many cases [6,7].Currently there are no effective systemic drug therapies for primary or metastatic UM [8,9].The median age at diagnosis is 62 years and the incidence of UM in males and females, and whether there is right or left eye involvement, is similar [10]. Underlying risk factors for UM include melanocytosis, melanocytoma, neurofibromatosis and the presence of atypical nevi [11][12][13][14]. Race is also a significant risk factor with a 150-fold greater incidence in fair-skinned over dark-skinned populations [15]. The incidence of UM in European countries varies wi...

GNAQ and GNA11 Genes: A Comprehensive Review on Oncogenesis, Prognosis and Therapeutic Opportunities in Uveal Melanoma

“…The growing relevance of this therapeutic strategy is now evidenced by the numerous relevant papers that regularly report the latest results and knowledge on UM-targeted therapies [73][74][75][76] (Figure 1, Table S1) mutations in MUM specimens, and the commonly mutated GNAQ/GNA11 genes in survival after development of systemic metastasis. They found similar rate frequencies for both genes in patients, where mutations in GNAQ and GNA11 genes were observed in 44.8% and 47.1% of patients, respectively [35].…”

“…The growing relevance of this therapeutic strategy is now evidenced by the numerous relevant papers that regularly report the latest results and knowledge on UM-targeted therapies [73][74][75][76] (Figure 1, Table S1)…”

Recent Advances and Challenges in Uveal Melanoma Immunotherapy

“…However, they may act as feasible treatments for a small portion of patients with UM. To date, factors influencing individual responses to ipilimumab are unknown [59].…”

The ever‐expanding landscape of cancer therapeutic approaches

“…Metastasis is common, and treatments require new drug targets. This topic is reviewed by Janney Wang and colleagues [21] who provide an extensive overview of agents that have been evaluated for the treatment of UM and discuss potential new targets for metastatic disease.…”