Faculty of Medicine and Health, Sydney Pharmacy School, The University of Sydney, NSW, Australia.
Faculty of Medicine, The University of New South Wales, Sydney, NSW, Australia.
FEBS J. 2021 Nov;288(21):6226-6249. doi: 10.1111/febs.15869. Epub 2021 May 1.
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 utilise 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 which 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 individualised tumour profiling. It would also be important to characterise 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.
葡萄膜黑色素瘤 (UM) 是成年人中最常见的原发性眼内恶性肿瘤。UM 发生的重要细胞遗传学和遗传风险因素包括 3 号染色体单体性、鸟嘌呤核苷酸结合蛋白 GNAQ/GNA11 的突变以及 BRACA1 相关蛋白 1 (BAP 1) 的缺失。大多数原发性 UM 采用放疗保守治疗，但对于大肿瘤则需要进行眼球摘除术。尽管局部控制效果显著，但仍有高达 50%的 UM 患者发生转移，而目前尚无有效的治疗方法。尽管针对其他癌症（包括一系列信号转导通路抑制剂）开发的靶向治疗药物在 UM 中很少产生显著效果，但尝试利用这些药物的情况仍时有发生。同样，在治疗 UM 中，对皮肤黑色素瘤有效的免疫疗法的应用也令人失望。已经启动的其他方法包括蛋白酶体抑制剂和组蛋白去乙酰化酶抑制剂，这些药物已被批准用于治疗其他癌症。尽管如此，这些治疗方法在 UM 中偶尔也会产生一些积极的结果。此外，UM 的联合治疗方法也取得了一些积极的进展。通过个体化肿瘤分析，确定如何有效地将这些疗法应用于 UM 将具有重要价值。此外，对 UM 肿瘤进行特征分析以区分其与其他类型癌症的潜在进展驱动因素也很重要。最近在 UM 肿瘤中发现了新型激酶和转移性基因，这使得开发新的 UM 特异性治疗方法成为可能。
