Molecular Mechanism and Therapy for Ocular Melanoma

摘要 葡萄膜黑色素瘤是成人最常见的眼部肿瘤。它蕴藏着截然不同的基因突变 与皮肤黑色素瘤的情况不同。肝转移在葡萄膜黑色素瘤中很常见，并与 预后很差，平均存活几个月。目前还没有治疗转移性葡萄膜的方法。 黑色素瘤。GNAQ和GNA11的激活突变是最重要的癌症驱动因素，大约 80%的葡萄膜黑色素瘤存在GNAQ或GNA11突变。我们最近的研究表明， 突变体GNAQ/11可有效激活YAP癌蛋白，YAP癌蛋白是河马肿瘤的关键成分 抑制子途径。此外，yap活性的升高对葡萄膜黑色素瘤细胞的肿瘤生长是必不可少的。 包含GNAQ/11的激活突变。除GNAQ/11外，BAP1、SF3B1和EIF1AX的突变 在葡萄膜黑色素瘤中也经常以相互排斥的方式出现。然而，一个机械主义者 对葡萄膜黑色素瘤中这些基因及其功能相互作用的了解在很大程度上是未知的。这个 该项目的主要目标是确定葡萄膜黑色素瘤中常见突变基因的作用。 以及它们在促进葡萄膜黑色素瘤发生中的功能相互作用。我们还致力于描述和描述 验证治疗葡萄膜黑色素瘤的潜在治疗靶点和工具。

Abstract Uveal melanoma is the most common ocular tumor in adults. It harbors genetic mutations very different from those seen in cutaneous melanoma. Liver metastasis is common in uveal melanoma and contributes to the very poor prognosis with average survival of several months. Currently there is no treatment for metastatic uveal melanoma. Activating mutations in GNAQ and GNA11 are the most important cancer drivers, as approximately 80% of uveal melanomas have mutations in either GNAQ or GNA11. Our recent studies have shown that the mutant GNAQ/11 potently activates the YAP oncoprotein, which is a key component of the Hippo tumor suppressor pathway. Moreover, the elevated YAP activity is essential for tumor growth of uveal melanoma cells containing an activating mutation in GNAQ/11. Besides GNAQ/11, mutations in BAP1, SF3B1, and EIF1AX are also frequently observed in uveal melanoma in a mutually exclusive manner. However, a mechanistic understanding of these genes in uveal melanoma and their functional interactions are largely unknown. The major goals of this project are to determine the contributions of the genes commonly mutated in uveal melanoma and their functional interaction in promoting tumorigenesis of uveal melanoma. We also aim to characterize and validate potential therapeutic targets and tools for treatment of uveal melanoma.