Pharmacological inhibition of the LIF/LIFR autocrine loop reveals vulnerability of ovarian cancer cells to ferroptosis.

Of all gynecologic cancers, epithelial-ovarian cancer (OCa) stands out with the highest mortality rates. Despite all efforts, 90% of individuals who receive standard surgical and cytotoxic therapy experience disease recurrence. The precise mechanism by which leukemia inhibitory factor (LIF) and its receptor (LIFR) contribute to the progression of OCa remains unknown. Analysis of cancer databases revealed that elevated expression of LIF or LIFR was associated with poor progression-free survival of OCa patients and a predictor of poor response to chemotherapy. Using multiple primary and established OCa cell lines or tissues that represent five subtypes of epithelial-OCa, we demonstrated that LIF/LIFR autocrine signaling is active in OCa. Moreover, treatment with LIFR inhibitor, EC359 significantly reduced OCa cell viability and cell survival with an IC50 ranging from 5-50 nM. Furthermore, EC359 diminished the stemness of OCa cells. Mechanistic studies using RNA-seq and rescue experiments unveiled that EC359 primarily induced ferroptosis by suppressing the glutathione antioxidant defense system. Using multiple in vitro, ex vivo and in vivo models including cell-based xenografts, patient-derived explants, organoids, and xenograft tumors, we demonstrated that EC359 dramatically reduced the growth and progression of OCa. Additionally, EC359 therapy considerably improved tumor immunogenicity by robust CD45+ leukocyte tumor infiltration and polarizing tumor-associated macrophages (TAMs) toward M1 phenotype while showing no impact on normal T-, B-, and other immune cells. Collectively, our findings indicate that the LIF/LIFR autocrine loop plays an essential role in OCa progression and that EC359 could be a promising therapeutic agent for OCa.

The LIFR Inhibitor EC359 Effectively Targets Type II Endometrial Cancer by Blocking LIF/LIFR Oncogenic Signaling.

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.

Effect of receiving a customizable brochure on breast cancer patients' knowledge about their diagnosis and treatment: A randomized clinical trial.

BACKGROUND: Patients' lack of knowledge about their own disease may function as a barrier to shared decision-making and well-being. This study aimed to evaluate the impact of written educational materials on breast cancer patients. METHODS: This multicenter, parallel, unblinded, randomized trial included Latin American women aged ≥18 years with a recent breast cancer diagnosis yet to start systemic therapy. Participants underwent randomization in a 1:1 ratio to receive a customizable or standard educational brochure. The primary objective was accurate identification of molecular subtype. Secondary objectives included identification of clinical stage, treatment options, participation in decision-making, perceived quality of information received, and illness uncertainty. Follow-up occurred at 7-21 and 30-51 days post-randomization. CLINICALTRIALS: gov identifier: NCT05798312. RESULTS: One hundred sixty-five breast cancer patients with a median age of 53 years and 61 days from diagnosis were included (customizable: 82; standard: 83). At first available assessment, 52%, 48%, and 30% identified their molecular subtype, disease stage, and guideline-endorsed systemic treatment strategy, respectively. Accurate molecular subtype and stage identification were similar between groups. Per multivariate analysis, customizable brochure recipients were more likely to identify their guideline-recommended treatment modalities (OR: 4.20,p = 0.001). There were no differences between groups in the perceived quality of information received or illness uncertainty. Customizable brochure recipients reported increased participation in decision-making (p = 0.042). CONCLUSIONS: Over one third of recently diagnosed breast cancer patients are incognizant of their disease characteristics and treatment options. This study demonstrates a need to improve patient education and shows that customizable educational materials increase patients' understanding of recommended systemic therapies according to individual breast cancer characteristics.

Structure-Activity Relationships of the Enterococcal Cytolysin.

Enterococcal cytolysin is a hemolytic virulence factor linked to human disease and increased patient mortality. Produced by pathogenic strains of Enterococcus faecalis, cytolysin is made up of two small, post-translationally modified peptides called CylLL" and CylLS". They exhibit a unique toxicity profile where lytic activity is observed for both mammalian cells and Gram-positive bacteria that is dependent on the presence of both peptides. In this study, we performed alanine substitution of all residues in CylLL" and CylLS" and determined the effect on both activities. We identified key residues involved in overall activity and residues that dictate cell type specificity. All (methyl)lanthionines as well as a Gly-rich hinge region were critical for both activities. In addition, we investigated the binding of the two subunits to bacterial cells suggesting that the large subunit CylLL" has stronger affinity for the membrane or a target molecule therein. Genome mining identified other potential two-component lanthipeptides and provided insights into potential evolutionary origins.