G alpha-q/11 Signaling and Inhibition in Ocular Melanoma

项目摘要 葡萄膜黑色素瘤(UM)是成人最常见的眼内肿瘤。近一半的UM患者 患上转移性疾病并存活一年或更短时间。目前还没有有效的治疗方法。当前干预措施 损害或破坏视力，但不能改善由转移性疾病引起的发病率或死亡率。临床试验 细胞毒性化疗药物和免疫检查点抑制剂的疗效甚微。突变型 到目前为止，在约90%的UM患者中推动肿瘤发生的GαQ/11结构性活性形式是 无法下药。这些癌蛋白下游的信号分子的抑制剂未能证明 显著的临床益处。有效的治疗可能需要突破，使直接靶向 构成活性的GαQ/11或必要的但尚未确定的下游信号级联。 这个项目填补了这些空白，因为它首次证明了构成活性的GαQ/11可以是 在药理上被困在不活跃的GDP结合状态，从而减弱下游信号。这个 抑制剂使GαQ/11驱动的UM细胞停止生长、死亡或重新分化为黑素细胞。 而对BRAF驱动的UM细胞无影响。经抑制剂处理的UM细胞揭示了一种新的 结构活性G-αQ/11信号通路拮抗表观遗传沉默的致癌机制 由多梳抑制复合体2(PRC2)介导，推动去分化。 在这些突破的基础上，将追求以下目标：1)寻找新的可用药靶点 在UM细胞中调节GαQ/11和PrC2之间的信号传递；2)决定是否 GαQ/11抑制剂在原发和转移性UM小鼠模型中提供了保护视力的治疗益处； 以及3)通过确定人类原发UM肿瘤的哪些临床亚类来为临床试验做准备 对GαQ/11抑制剂的体外反应。总而言之，这个项目提供了前所未有的机会 确定直接药理抑制突变的成分活性GαQ/11是否能提供 治疗UM的第一个有效且可能保留视力的治疗方案。

Project Summary Uveal melanoma (UM) is the most common intraocular tumor in adults. Nearly half of UM patients develop metastatic disease and survive one year or less. No effective therapy exists. Current interventions impair or destroy vision, yet do not improve morbidity or mortality caused by metastatic disease. Clinical trials of cytotoxic chemotherapeutics and immune checkpoint inhibitors have shown little efficacy. Mutant constitutively active forms of Gαq/11 that drive oncogenesis in ~90% of UM patients thus far have been undruggable. Inhibitors of signaling molecules downstream of these oncoproteins have failed to demonstrate significant clinical benefit. Effective therapy may require breakthroughs that enable direct targeting of constitutively active Gαq/11 or necessary but as yet unidentified downstream signaling cascades. This project fills these gaps by showing for the first time that constitutively active Gαq/11 can be trapped pharmacologically in the inactive GDP-bound state, thereby attenuating downstream signaling. The inhibitor causes Gαq/11-driven UM cells to arrest growth, die, or re-differentiate into melanocytic cells, whereas it has no effect on BRAF-driven UM cells. Inhibitor-treated UM cells has revealed a novel oncogenesis mechanism in which signaling by constitutively active Gαq/11 antagonizes epigenetic silencing mediated by polycomb repressive complex 2 (PRC2) to drive de-differentiation. Based on these breakthroughs, the following Aims will be pursued: 1) Identify novel druggable targets that mediate signaling between constitutively active Gαq/11 and PRC2 in UM cells; 2) Determine whether the Gαq/11 inhibitor provides vision-sparing therapeutic benefit in mouse models of primary and metastatic UM; and 3) Set the stage for clinical trials by determining which clinical subclasses of human primary UM tumors respond ex vivo to the Gαq/11 inhibitor. In summary, this project provides unprecedented opportunity to determine whether direct pharmacological inhibition of mutant constitutively active Gαq/11 could provide the first effective and potentially vision-sparing therapeutic option for treating UM.