The Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York.
Linnaeus Therapeutics, Haddonfield, New Jersey.
Cancer Res Commun. 2023 Apr 5;3(4):540-547. doi: 10.1158/2767-9764.CRC-22-0399. eCollection 2023 Apr.
Uveal melanoma is the most common primary intraocular malignancy in adults and has a high incidence of metastatic disease. Current treatments have shown limited clinical activity in patients with uveal melanoma with metastasis and there is an urgent need for new effective therapies. Recent findings have shown that women with uveal melanoma have better survival rates than men. The G protein-coupled estrogen receptor-1 (GPER) has distinct functions from those of the classic estrogen receptors ERα/β and its activation by specific agonists has tumor-suppressive roles in several cancers. However, the role of GPER had not previously been investigated in uveal melanoma. We demonstrated that downregulation of GPER in uveal melanoma cells decreased expression of p53 and stimulated cell growth. In contrast, the clinical GPER agonist, LNS8801, upregulated p53 and p21, induced melanocytic differentiation markers, inhibited cell proliferation and cell migration, and induced apoptosis. Furthermore, LNS8801 treatment arrested the cells in G-M-phase of the cell cycle with concomitant activation of mitotic markers and disruption of the mitotic spindle apparatus. LNS8801 significantly inhibited tumor growth of uveal melanoma xenografts , suggesting that GPER agonists may be a novel treatment for uveal melanoma.
Current treatments against metastatic uveal melanoma have shown limited clinical activity and there is an urgent need for effective therapies. Here, we demonstrate that the GPER agonist LNS8801 induced both GPER-dependent and GPER-independent effects and elicited potent anticancer activities and . Our results complement and support the ongoing clinical trial of LNS8801 in advanced uveal melanoma.
葡萄膜黑色素瘤是成年人中最常见的原发性眼内恶性肿瘤，其转移性疾病的发病率很高。目前的治疗方法在转移性葡萄膜黑色素瘤患者中的临床疗效有限，因此迫切需要新的有效治疗方法。最近的研究结果表明，女性葡萄膜黑色素瘤患者的生存率高于男性。G 蛋白偶联雌激素受体-1（GPER）具有与经典雌激素受体 ERα/β不同的功能，其特定激动剂的激活在几种癌症中具有肿瘤抑制作用。然而，GPER 在葡萄膜黑色素瘤中的作用尚未被研究过。我们证明，葡萄膜黑色素瘤细胞中 GPER 的下调降低了 p53 的表达并刺激了细胞生长。相比之下，临床 GPER 激动剂 LNS8801 上调了 p53 和 p21，诱导黑素细胞分化标志物，抑制细胞增殖和细胞迁移，并诱导细胞凋亡。此外，LNS8801 治疗使细胞停滞在细胞周期的 G-M 期，同时激活有丝分裂标志物并破坏有丝分裂纺锤体装置。LNS8801 显著抑制了葡萄膜黑色素瘤异种移植瘤的生长，这表明 GPER 激动剂可能是治疗葡萄膜黑色素瘤的一种新方法。
目前针对转移性葡萄膜黑色素瘤的治疗方法显示出有限的临床疗效，因此迫切需要有效的治疗方法。在这里，我们证明了 GPER 激动剂 LNS8801 诱导了 GPER 依赖性和非依赖性效应，并产生了强大的抗癌活性。我们的结果补充和支持了 LNS8801 在晚期葡萄膜黑色素瘤中的临床研究。
