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Objectives: Endometrial cancer is the most common gynecologic malignancy in women. Of the two histological subtypes of endometrial cancer described, Type II tumors are biologically more aggressive and convey a less favorable prognosis when compared to Type I tumors. Novel therapeutics for treatment of Type II endometrial cancer are needed. Leukemia Inhibitory Factor Receptor (LIFR) and its ligand, LIF, play a critical role in cancer progression, metastasis, stem cell maintenance, and therapy resistance. Our recent studies revealed high levels of LIF and its receptor LIFR are associated with poor survival in endometrial cancer patients. We evaluated the efficacy of EC359, a novel small molecule inhibitor of the LIF receptor, against Type II Endometrial cancer cells. Methods: Primary and established cell lines were utilized in this study. Established cell lines were purchased from the American Type Culture Collection (ATCC CRL-1622). All primary samples were collected through the UT Health San Antonio tumor registry under IRB approval. The recently developed LIFR inhibitor, EC359, was used to elucidate the therapeutic utility of targeting the LIF/LIFR pathway in Type II endometrial cancer. In vitro activity was tested using MTT, colony formation, invasion, and apoptosis assays. Mechanistic studies were conducted using Western blot, reporter gene assays, and RT-qPCR analysis. Patient-derived xenograft (PDX) models were used for preclinical evaluation and toxicity. Results: Treatment of established and primary endometrial cancer cells with the LIFR inhibitor EC359 significantly reduced cell viability, long-term cell survival, invasion, and promoted apoptosis. Treatment with EC359 attenuated the activation of LIF/LIFR driven pathways including STAT3, mTOR, and AKT. EC359 significantly reduced tumor progression in patient derived xenograft model. Conclusions: These data support EC359 as a potential novel small molecule therapeutic for treatment of Type II Endometrial cancer.

Endometrial cancer (ECa) is the most common female gynecologic cancer. When comparing the two histological subtypes of endometrial cancer, Type II tumors are biologically more aggressive and have a worse prognosis than Type I tumors. Current treatments for Type II tumors are ineffective, and new targeted therapies are urgently needed. LIFR and its ligand, LIF, have been shown to play a critical role in the progression of multiple solid cancers and therapy resistance. The role of LIF/LIFR in the progression of Type II ECa, on the other hand, is unknown. We investigated the role of LIF/LIFR signaling in Type II ECa and tested the efficacy of EC359, a novel small-molecule LIFR inhibitor, against Type II ECa. The analysis of tumor databases has uncovered a correlation between diminished survival rates and increased expression of leukemia inhibitory factor (LIF), suggesting a potential connection between altered LIF expression and unfavorable overall survival in Type II ECa. The results obtained from cell viability and colony formation assays demonstrated a significant decrease in the growth of Type II ECa LIFR knockdown cells in comparison to vector control cells. Furthermore, in both primary and established Type II ECa cells, pharmacological inhibition of the LIF/LIFR axis with EC359 markedly decreased cell viability, long-term cell survival, and invasion, and promoted apoptosis. Additionally, EC359 treatment reduced the activation of pathways driven by LIF/LIFR, such as AKT, mTOR, and STAT3. Tumor progression was markedly inhibited by EC359 treatment in two different patient-derived xenograft models in vivo and patient-derived organoids ex vivo. Collectively, these results suggest LIFR inhibitor EC359 as a possible new small-molecule therapeutics for the management of Type II ECa.