Endometrial cancer (EC) is the fourth most common cancer in women. Advanced-stage EC has limited treatment options with a poor prognosis. There is an unmet need for the identification of actionable drivers for the development of targeted therapies in EC. Leukemia inhibitory factor receptor (LIFR) and its ligand LIF play a major role in cancer progression, metastasis, stemness, and therapy resistance. However, little is known about the functional significance of the LIF/LIFR axis in EC progression. In this study using endometrial tumor tissue arrays, we identified that expression of LIF, LIFR is upregulated in EC. Knockout of LIFR using CRISPR/Cas9 in two different EC cells resulted in a significant reduction of their cell viability and cell survival. In vivo studies demonstrated that LIFR-KO significantly reduced EC xenograft tumor growth. Treatment of established and primary patient-derived EC cells with a novel LIFR inhibitor, EC359 resulted in the reduction of cell viability with an IC50 in the range of 20–100 nM and induction of apoptosis. Further, treatment with EC359 reduced the spheroid formation of EC cancer stem cells and reduced the levels of cancer stem cell markers SOX2, OCT4, NANOG, and Axin2. Mechanistic studies demonstrated that EC359 treatment attenuated the activation of LIF-LIFR driven pathways, including STAT3 and AKT/mTOR signaling in EC cells. Importantly, EC359 treatment resulted in a significant reduction of the growth of EC patient-derived explants ex vivo, EC cell line-derived xenografts, and patient-derived xenografts in vivo. Collectively, our work revealed the oncogenic potential of the LIF/LIFR axis in EC and support the utility of LIFR inhibitor, EC359, as a novel targeted therapy for EC via the inhibition of LIF/LIFR oncogenic signaling.

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diastolic flow (iAEDF), donor UA systolic velocity/diastolic velocity (SD ratio), estimated fetal weight (EFW) percent discordance, and cervical length were associated with the outcome. Multiple logistic regression modeling identified donor UA forward flow (OR 2.38 [95%CI 1.03-5.56], p¼0.0433) and cervical length (cm) (1.43 [95% CI 1.02-2.00], p¼0.0395) as the only associated factors, yielding a cstatistic of 0.64. CONCLUSION: With 88% overall dual survivorship and 33 weeks mean GA at delivery, laser surgery for stage I TTTS remains a reasonable option. Robust predictors of favorable outcomes that could be incorporated into preoperative counseling were not identified.

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Background: Endometrial cancer (EC) is the fourth most common cancer in women. Approximately 80% of EC belong to the endometroid-EC subtype and are driven by estrogen signaling. Advanced-stage EC has limited treatment options with poor prognosis. There is an urgent need for the identification of actionable drivers as new targets for treating advance stage EC. Leukemia inhibitory factor receptor (LIFR) and its ligand LIF plays a major role in cancer progression, metastasis, stemness, and therapy resistance. Published and our preliminary data suggest a critical role of the LIF-LIFR signaling axis in EC progression. The objective of this study is to test the utility of targeting the LIF/LIFR axis using a novel LIFR inhibitor, EC359. Methods: We used multiple established and primary EC cells to test the utility LIFR inhibitor, EC359 in treating EC. CRISPR/Cas9 system was used to generate LIFR KO EC cells. In vitro activity was tested using Cell-Titer Glo, MTT, invasion, and apoptosis assays. Mechanistic studies were conducted using Western blot, reporter gene assays, and RNA-seq analysis. EC cell-derived xenograft (CDX) and patient-derived explant (PDEX) models were used for preclinical evaluation and toxicity. Results: EC359 treatment of seven EC cells showed anti-proliferative effects in MTT cell viability assays with an IC50 of 25-100 nM. Further, EC359 treatment reduced invasiveness, stemness, and promoted apoptosis of EC cells. The activity of EC359 is dependent on LIF/LIFR expression in EC cells. CRISPR mediated knockout of LIFR significantly abolished EC359 activity. In vivo xenograft studies using Ishikawa-vector or LIFR-KO cells demonstrated that LIFR-KO significantly reduced EC tumor growth, and tumor weights. Further, EC359 treatment attenuated the activation of LIF/LIFR driven pathways, including STAT3, AKT-mTOR signaling. Mechanistic studies using RNA-seq revealed that EC359 significantly upregulated 213 genes and down regulated 126 genes. Pathway analyses of differential genes revealed enrichment in the apoptotic pathways upon EC359 treatment. EC359 (5mg/kg body weight) treatment significantly reduced CDX tumor progression and reduced proliferation in PDEX models. Conclusions: Collectively, these data support EC359 as a novel targeted therapy for EC by inhibiting LIF/LIFR oncogenic signaling pathway. Citation Format: Weiwei Tang, Kumaraguruparan Ramasamy, Sureshkumar M. Pillai, Bindu Santhamma, Swapna Konda, Prabhakar P. Vekata, Logan Blankenship, Junhao Liu, Zexuan Liu, Kristin A. Altwegg, Behnam Ebrahimi, Uday P. Pratap, Xiaonan Li, Edward Kost, Gangadhara R. Sareddy, Ratna K. Vadlamudi, Hareesh B. Nair, Rajeshwar R. Tekmal, Suryavathi Viswanadhapalli. Therapeutic targeting of endometrial cancer with novel LIFR inhibitor EC359 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1253.

Background: ADT results in metabolic syndrome, characterized by hyperinsulinemia, insulin resistance and obesity. The hyperinsulinemia may result in ADT resistance; therefore preventing metabolic syndrome could have a therapeutic impact on PCa. Metformin decreases glucose & insulin by inhibiting hepatic gluconeogenesis. There is preclinical evidence for additional antineoplastic activity due to mTOR inhibition secondary to AMPK activation. Methods: We analyzed serum and PBMC from a recently completed clinical study of men with advanced PCa on ADT that were randomized 1:1 to metformin at 500mg TID or color matched placebo. Subjects serum insulin/glucose, metformin levels, weight and waist circumference (WC) was assessed at baseline, week 12 and 28. The primary endpoint of study was the metabolic consequences of metformin vs placebo cohort. Secondary endpoints were PSA response and PBMC analysis of downstream target of mTOR, phospho-S6 kinase. Results: There were 36 evaluable men. The mean age on study was 68.4. Mean weight, WC and insulin at baseline in metformin cohort was 187 lbs, 41.14 cm and 10.03 mIU/L respectively, and 177.65 lbs, 40.52 cm and 8.02 mIU/L in placebo cohort. An increase in mean weight, WC and insulin levels was seen in both cohorts. At week 12 and 28, no statistical difference in weight, WC and insulin was observe in either cohort. Four men randomized to metformin had undetectable serum drug levels despite drug-diary suggesting compliance; excluding them did not result in significant metabolic change. Assessing efficacy, 50% in metformin and 53.3% in placebo cohort achieved undetectable PSA at week 28; difference not statistically significant. PBMC analysis demonstrated variable down-regulation of phospho-S6 kinase in the metformin cohort. Conclusion: This study detected no impact of MET addition to ADT on the risk of metabolic syndrome and no additional anti-tumor effects. Control of hyperinsulinemia related to diabetes by MET does not necessarily imply MET has a similar action on hyperinsulinemia due to ADT. Citation Format: Devalingam Mahalingam, Salih Hanni, Christos Fountzilas, Joel Michalek, John Sarantopoulos, Sureshkumar Mulampurath Achuthan Pillai, John Kuhn, Michael Pollak, Ian Thompson. Metformin to prevent metabolic syndrome associated with androgen deprivation therapy (ADT): Metabolic analysis from a placebo-controlled study of metformin in non-diabetic men initiating ADT for advanced prostate cancer (PCa) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3269.

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