Abstract 1852: G protein-coupled estrogen receptor-1 agonist LNS8801 induces mitotic arrest and cell death in uveal melanoma cells

Abstract

Abstract Uveal melanoma (UM) is the most common primary intraocular malignant tumor in adults. Nearly 50% of the patients develop hepatic metastasis, and when this occurs the 1-year survival rate is 12 months. While the primary tumor can be treated with radiotherapy and surgery, current treatments for metastatic disease have shown limited clinical activity in UM patients and there is an urgent need for new effective therapies. Recent reports have shown that male patients have more metastases than female patients, and the time from the diagnosis until development of metastases was shorter, suggesting a potential role of female hormones in disease progression. The G-protein-coupled estrogen receptor-1 (GPER) has distinct functions from those of the classic estrogen receptors ERα/β and its activation with a specific agonist has tumor-suppressive roles in several cancers. Here, we demonstrate that the novel clinical GPER agonist, LNS8801 (Linnaeus Therapeutics), has potent anticancer activities in UM cells including inhibition of cell migration and cell proliferation. LNS8801 treatment induced a G2/M cell cycle arrest due to disruption of tubulin polymerization and defective mitotic spindle formation. There was a time-dependent increase of mitotic proteins, such as phosphorylated aurora-A, aurora-B and histone-3, while c-Myc and phospho-Rb were downregulated. The drug treatment also induced significant cell death, as detected by caspase 3/7 activation and PARP cleavage. Finally, LNS8801 inhibited tumor growth in a UM xenograft model in vivo. In conclusion, our studies suggest that GPER agonists may be a novel treatment for uveal melanoma, and clinical trials with the GPER agonist LNS8801 are warranted and currently underway. Citation Format: Grazia Ambrosini, Christopher A. Natale, Gary K. Schwartz. G protein-coupled estrogen receptor-1 agonist LNS8801 induces mitotic arrest and cell death in uveal melanoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1852.