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。它所携带的基因突变 与皮肤黑色素瘤中所见不同。肝转移在葡萄膜黑色素瘤中是常见的，并有助于葡萄膜黑色素瘤的发生。 预后极差，平均存活数个月。目前还没有治疗转移性葡萄膜炎的方法 黑素瘤GNAQ和GNA 11中的激活突变是最重要的癌症驱动因素，大约 80%的葡萄膜黑色素瘤在GNAQ或GNA 11中存在突变。我们最近的研究表明， 突变体GNAQ/11有效激活雅普癌蛋白，这是Hippo肿瘤的关键成分 抑制子途径此外，升高的雅普活性对于葡萄膜黑色素瘤细胞的肿瘤生长是必需的 在GNAQ/11中含有激活突变。除GNAQ/11外，BAP 1、SF 3B 1和EIF 1AX的突变也是一个重要的基因突变。 在葡萄膜黑色素瘤中也经常以相互排斥的方式观察到。然而，一个机械的 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。的 这个项目的主要目标是确定葡萄膜黑色素瘤中常见的突变基因的作用 以及它们在促进葡萄膜黑色素瘤发生中的功能相互作用。我们还旨在描述和 验证用于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.