Abstract 4688: EC359, A new therapeutic drug for the treatment of low grade serous ovarian cancer
Authors: Yasmin Lyons, William Cole Arnold, Behnam Ebrahimi, Bindu Santhamma, Edward R. Kost, Hareesh B. Nair, Suryavathi Viswanadhapalli, Ratna K. Vadlamudi
Journal: Cancer Research (2024)

Abstract Background: Ovarian cancer (OCa) is the deadliest of all gynecologic cancers in the United States. About 10% of all cases of serous ovarian cancer have the unusual histology named low-grade serous carcinomas (LGSOC), that has a distinct clinical behavior with a unique molecular landscape. LGSOC is characterized by a younger age at diagnosis, indolent progression, and chemotherapy resistance. BRAF and KRAS mutations occur in 33% and 35% of LGSOC cases, respectively. LGSOC is frequently detected when the malignancy is in advanced stage and LGSOC relapses in about 70% of patients with advanced disease. Therefore, new targeted therapies are required. Since LGSOC uniquely expresses mutations of either BRAF or KRAS, and because Leukemia Inhibitor Factor (LIF) expression is induced by oncogenes such as KRAS, we reason that the LIF/LIFR axis represents a unique target for treating LGSOC. The objective of this study is to test the utility of blocking LIF/LIFR axis using LIFR inhibitor EC359 in treating LGSOC. Methods: The expression of LIF and its receptor LIFR was profiled using multiple established LGSOC cells and primary LGSOC model cells. The effects of EC359 on LGSOC cells were evaluated using cell viability, colony formation, and apoptosis assays. Mechanistic investigations were conducted with Western blotting, reporter assays and RT-qPCR analysis. The in vivo efficacy of LIFR inhibitor EC359 as a targeted therapy was investigated using LGSOC cell-based xenografts. Results: Western blot analysis confirmed expression of LIFR and LIF in established LGSOC and primary LGSOC cells and functional autocrine loop of LIF/LIFR signaling. The treatment with the LIFR inhibitor EC359 significantly reduced LGSOC cell viability, cell survival, and increased apoptosis. The activation of downstream LIFR signaling including STAT3, mTOR, AKT, and p42/44 MAPKs markedly decreased by EC359 treatment. EC359 enhanced the efficacy of trametinib, a currently used medication of LGSOC. EC359+trametinib as a combination therapy showed more efficacy over monotherapy of EC359 or trametinib in reducing cell viability and colony formation. Using cell-based xenograft and PDX models, we demonstrated that the EC359 at 5mg/kg dose significantly reduced the LGSOC xenograft growth compared to the vehicle control. Conclusions: Together, our findings support the existence of LIF/LIFR autocrine loops, and EC359 is a viable treatment option for LGSOC. Citation Format: Yasmin Lyons, William Cole Arnold, Behnam Ebrahimi, Bindu Santhamma, Edward R. Kost, Hareesh B. Nair, Suryavathi Viswanadhapalli, Ratna K. Vadlamudi. EC359, A new therapeutic drug for the treatment of low grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4688.