Sesamolin serves as an MYH14 inhibitor to sensitize endometrial cancer to chemotherapy and endocrine therapy via suppressing MYH9/GSK3ß/ß-catenin signaling.

BACKGROUND: Endometrial cancer (EC) is one of the most common gynecological cancers. Herein, we aimed to define the role of specific myosin family members in EC because this protein family is involved in the progression of various cancers. METHODS: Bioinformatics analyses were performed to reveal EC patients' prognosis-associated genes in patients with EC. Furthermore, colony formation, immunofluorescence, cell counting kit 8, wound healing, and transwell assays as well as coimmunoprecipitation, cycloheximide chase, luciferase reporter, and cellular thermal shift assays were performed to functionally and mechanistically analyze human EC samples, cell lines, and a mouse model, respectively. RESULTS: Machine learning techniques identified MYH14, a member of the myosin family, as the prognosis-associated gene in patients with EC. Furthermore, bioinformatics analyses based on public databases showed that MYH14 was associated with EC chemoresistance. Moreover, immunohistochemistry validated MYH14 upregulation in EC cases compared with that in normal controls and confirmed that MYH14 was an independent and unfavorable prognostic indicator of EC. MYH14 impaired cell sensitivity to carboplatin, paclitaxel, and progesterone, and increased cell proliferation and metastasis in EC. The mechanistic study showed that MYH14 interacted with MYH9 and impaired GSK3ß-mediated ß-catenin ubiquitination and degradation, thus facilitating the Wnt/ß-catenin signaling pathway and epithelial-mesenchymal transition. Sesamolin, a natural compound extracted from Sesamum indicum (L.), directly targeted MYH14 and attenuated EC progression. Additionally, the compound disrupted the interplay between MYH14 and MYH9 and repressed MYH9-regulated Wnt/ß-catenin signaling. The in vivo study further verified sesamolin as a therapeutic drug without side effects. CONCLUSIONS: Herein, we identified that EC prognosis-associated MYH14 was independently responsible for poor overall survival time of patients, and it augmented EC progression by activating Wnt/ß-catenin signaling. Targeting MYH14 by sesamolin, a cytotoxicity-based approach, can be applied synergistically with chemotherapy and endocrine therapy to eventually mitigate EC development. This study emphasizes MYH14 as a potential target and sesamolin as a valuable natural drug for EC therapy.

Proteogenomic insights into early-onset endometrioid endometrial carcinoma: predictors for fertility-sparing therapy response.

Endometrial carcinoma remains a public health concern with a growing incidence, particularly in younger women. Preserving fertility is a crucial consideration in the management of early-onset endometrioid endometrial carcinoma (EEEC), particularly in patients under 40 who maintain both reproductive desire and capacity. To illuminate the molecular characteristics of EEEC, we undertook a large-scale multi-omics study of 215 patients with endometrial carcinoma, including 81 with EEEC. We reveal an unexpected association between exposome-related mutational signature and EEEC, characterized by specific CTNNB1 and SIGLEC10 hotspot mutations and disruption of downstream pathways. Interestingly, SIGLEC10Q144K mutation in EEECs resulted in aberrant SIGLEC-10 protein expression and promoted progestin resistance by interacting with estrogen receptor alpha. We also identified potential protein biomarkers for progestin response in fertility-sparing treatment for EEEC. Collectively, our study establishes a proteogenomic resource of EEECs, uncovering the interactions between exposome and genomic susceptibilities that contribute to the development of primary prevention and early detection strategies for EEECs.

Real-world treatment patterns and clinical outcomes from a retrospective chart review study of patients with recurrent or advanced endometrial cancer who progressed following prior systemic therapy in Europe.

OBJECTIVE: To evaluate real-world treatment patterns and clinical outcomes in recurrent/advanced endometrial cancer patients who progressed following prior systemic therapy in clinical practice in Europe. DESIGN: Endometrial Cancer Health Outcomes-Europe (ECHO-EU) is a retrospective patient chart review study. SETTING: ECHO-EU is a multicentre study conducted in the UK, Germany, Italy, France and Spain. PARTICIPANTS: Patients with recurrent/advanced endometrial cancer who progressed between 1 July 2016 and 30 June 2019 following prior first-line systemic therapy were eligible and data were collected until last available follow-up through November 2021. PRIMARY AND SECONDARY OUTCOME MEASURES: Data collected included patient demographics, clinical and treatment characteristics, and clinical outcomes. Kaplan-Meier analyses were performed since initiation of second-line therapy to estimate time to treatment discontinuation, real-world progression-free survival (rwPFS) and overall survival (OS). RESULTS: A total of 475 patients were included from EU5 countries. Median age was 69 years at advanced endometrial cancer diagnosis, 78.7% had stage IIIB-IV disease, 45.9% had Eastern Cooperative Oncology Group status ≥2 at second-line therapy initiation. In second line, a majority of patients initiated either non-platinum-based chemotherapy (55.6%) or endocrine therapy (16.2%). Physician-reported real-world overall response rate (classified as complete or partial response) to second-line therapy was 34.5%, median rwPFS was 7.4 months (95% CI 6.2 to 8.0) and median OS was 11.0 months (95% CI 9.9 to 12.3). CONCLUSIONS: Patients had poor clinical outcomes with a median OS of <1 year and rwPFS of approximately 7 months, highlighting the significant unmet medical need in pretreated recurrent/advanced endometrial cancer patients. Novel therapies with potential to improve PFS and OS over conventional therapies could provide significant clinical benefit.

Predicting Response to Immunotargeted Therapy in Endometrial Cancer via Tumor Immune Microenvironment: A Multicenter, Observational Study.

Only one-third of patients with advanced MSS/pMMR endometrial cancer exhibit a lasting response to the combination treatment of Pembrolizumab and Lenvatinib. The combined administration of these two drugs is based on Lenvatinib's ability to modulate the tumor microenvironment, enabling Pembrolizumab to exert its effect. These findings underscore the importance of exploring tumor microenvironment parameters to identify markers that can accurately select candidates for this type of therapy. An open non-randomized observational association study was conducted at six clinical centers, involving a total of 28 patients with advanced MSS/pMMR endometrial cancer who received Pembrolizumab and Lenvatinib therapy. Using TSA-associated multiplex immunofluorescence, we analyzed the proportion of CD8+ T lymphocytes, CD20+ B lymphocytes, FoxP3+ T regulatory lymphocytes, and CD163+ macrophages in tumor samples prior to immunotargeted therapy. The percentage of CD20+ B lymphocytes and the CD8-to-CD20 lymphocytes ratio was significantly higher in patients who responded to treatment compared to non-responders (responders vs. non-responders: 0.24 (0.1-1.24)% vs. 0.08 (0.00-0.15)%, p = 0.0114; 1.44 (0.58-2.70) arb. unit vs. 19.00 (3.80-34.78) arb. unit, p = 0.0031). The sensitivity and specificity of these biomarkers were 85.71% and 70.59%, and 85.71% and 85.71%, respectively. The proportion of CD20+ B lymphocytes and the CD8-to-CD20 lymphocytes ratio in the stroma of endometrial cancer serves as both a prognostic marker of response to immunotargeted therapy and a prognostic factor for progression-free survival in patients.

Research progress on the mechanism of action of Salvia miltiorrhiza and its components in the treatment of endometrial carcinoma.

The incidence and mortality of endometrial carcinoma (EC) are increasing year by year. Although the curative effect of surgery and commonly used drugs is clear, it is accompanied by obvious side effects, and safe and effective means are urgently needed to promote the curative effect and decrease the toxicity of drugs. Traditional Chinese medicine has been passed down for thousands of years in China and has proved to be advantageous in the treatment of various cancers and the auxiliary enhancement and reduction of toxicity. This paper reviewed the role and internal mechanism of Salvia miltiorrhiza in preventing and treating endometrial carcinoma by referring to relevant literature and works, so as to more comprehensively understand and grasp the research status, effective components, curative effect and effective mechanism of S. miltiorrhiza in preventing and treating endometrial carcinoma, and provide ideas and basis for clinical use and basic research.

Immunotherapy in the treatment of advanced or recurrent endometrial cancer.

The standard treatment of patients with advanced or recurrent endometrial cancer has not significantly changed over the past few decades, reflecting a major unmet clinical need. Fortunately, the arrival of immune checkpoint inhibition is rapidly changing this dismal scenario. This review discusses the most recent results from clinical trials evaluating the use of immune checkpoint inhibitors, either as monotherapy or in combination therapy, in both the post-platinum and frontline settings. Additionally, a section is devoted to the future clinical development of immune checkpoint inhibitors in advanced or recurrent endometrial cancer.

Lenvatinib plus pembrolizumab in the patients with advanced previously treated endometrial cancer: A cost-effectiveness analysis in the United States and in China.

PURPOSE: To investigate the cost-effectiveness of lenvatinib plus pembrolizumab (LP) compared to chemotherapy as a second-line treatment for advanced endometrial cancer (EC) from the United States and Chinese payers' perspective. METHODS: In this economic evaluation, a partitioned survival model was constructed from the perspective of the United States and Chinese payers. The survival data were derived from the clinical trial (309-KEYNOTE-775), while costs and utility values were sourced from databases and published literature. Total costs, quality-adjusted life years (QALYs) and incremental cost-effectiveness ratio (ICER) were estimated. The robustness of the model was evaluated through sensitivity analyses, and price adjustment scenario analyses was also performed. RESULTS: Base-case analysis indicated that LP wouldn't be cost-effective in the United States at the WTP threshold of $200 000, with improved effectiveness of 0.75 QALYs and an additional cost of $398596.81 (ICER $531392.20). While LP was cost-effective in China, with improved effectiveness of 0.75 QALYs and an increased overall cost of $62270.44 (ICER $83016.29). Sensitivity analyses revealed that the above results were stable. The scenario analyses results indicated that LP was cost-effective in the United States when the prices of lenvatinib and pembrolizumab were simultaneously reduced by 61.95% ($26.5361/mg for lenvatinib and $19.1532/mg for pembrolizumab). CONCLUSION: LP isn't cost-effective in the patients with advanced previously treated endometrial cancer in the United States, whereas it is cost-effective in China. The evidence-based pricing strategy provided by this study could benefit decision-makers in making optimal decisions and clinicians in general clinical practice. More evidence about budget impact and affordability for patients is needed.

Dendritic cell vaccination combined with carboplatin/paclitaxel for metastatic endometrial cancer patients: results of a phase I/II trial.

Background: Metastatic endometrial cancer (mEC) continues to have a poor prognosis despite the introduction of several novel therapies including immune checkpoints inhibitors. Dendritic cell (DC) vaccination is known to be a safe immunotherapeutic modality that can induce immunological and clinical responses in patients with solid tumors. Platinum-based chemotherapy is known to act synergistically with immunotherapy by selectively depleting suppressive immune cells. Therefore, we investigated the immunological efficacy of combined chemoimmunotherapy with an autologous DC vaccine and carboplatin/paclitaxel chemotherapy. Study design: This is a prospective, exploratory, single-arm phase I/II study (NCT04212377) in 7 patients with mEC. The DC vaccine consisted of blood-derived conventional and plasmacytoid dendritic cells, loaded with known mEC antigens Mucin-1 and Survivin. Chemotherapy consisted of carboplatin/paclitaxel, given weekly for 6 cycles and three-weekly for 3 cycles. The primary endpoint was immunological vaccine efficacy; secondary endpoints were safety and feasibility. Results: Production of DC vaccines was successful in five out of seven patients. These five patients started study treatment and all were able to complete the entire treatment schedule. Antigen-specific responses could be demonstrated in two of the five patients who were treated. All patients had at least one adverse event grade 3 or higher. Treatment-related adverse events grade ≥3 were related to chemotherapy rather than DC vaccination; neutropenia was most common. Suppressive myeloid cells were selectively depleted in peripheral blood after chemotherapy. Conclusion: DC vaccination can be safely combined with carboplatin/paclitaxel in patients with metastatic endometrial cancer and induces antigen-specific responses in a minority of patients. Longitudinal immunological phenotyping is suggestive of a synergistic effect of the combination.

Transcriptome analysis of an AKT inhibitor-resistant endometrial cancer cell line.

BACKGROUND: Drug resistance in endometrial cancer (EC) is a serious problem and a barrier to improving prognosis. The PI3K/AKT/mTOR pathway is highly activated in EC and can serve as a potential therapeutic target. Inhibitors against AKT have been developed, but resistance to these inhibitors is a concern. This study aimed to establish AKT inhibitor resistant cell lines and identify differentially expressed genes (DEGs) between parental and AKT inhibitor resistant cell lines to understand the mechanism of drug resistance to AKT inhibitors in EC. METHODS: The sensitivity of eight EC cell lines to AKT inhibitor was analyzed. One of them was used to establish a drug-resistant cell line. DEGs were examined using RNA sequencing (RNA-seq). Furthermore, DEGs were comprehensively analyzed to identify hub genes. Hub genes were evaluated using quantitative real-time polymerase chain reaction. RESULTS: RNA-seq identified 617 DEGs. Hub genes were selected using bioinformatics analysis. The top 10 hub genes were TNF, CDH1, CCND1, COL1A1, CDH2, ICAM1, CAV1, THBS1, NCAM1, and CDKN2A. Relative mRNA expression was significantly upregulated for TNF, CDH1, CCND1, THBS1, p16INK4a, and p14ARF and significantly downregulated for CDH2, ICAM1, and NCAM1 in borussertib-resistant EC cell line. CONCLUSIONS: Drug resistance to AKT inhibitors may depend on genes related to cell adhesion-mediated resistance and transforming growth factor ß signaling.

Cost effectiveness of pembrolizumab plus lenvatinib compared with chemotherapy for treating previously treated advanced endometrial cancer in Sweden.

OBJECTIVE: Pembrolizumab plus lenvatinib was recently approved for the treatment of advanced or recurrent endometrial carcinoma in women with disease progression on or following prior treatment with a platinum­containing therapy in any setting, and who are not candidates for curative surgery or radiation (KEYNOTE-775/Study-309; NCT03517449). The objective was to assess the cost effectiveness of pembrolizumab plus lenvatinib compared with chemotherapy from a Swedish healthcare perspective. MATERIALS AND METHODS: A lifetime partitioned-survival model with three health states (progression free, progressed disease, death) was constructed. Chemotherapy was represented by paclitaxel or doxorubicin. Overall survival, progression-free survival, time on treatment, and utility data were obtained from KEYNOTE-775 (database lock: March 1, 2022). Costs (in 2020 Swedish Krona [SEK]) included drug acquisition and administration, health state, end of life, adverse event management, subsequent treatment, and societal (scenario analysis). Outcomes were calculated as quality-adjusted life-years (QALY) and life-years. Model results were presented as incremental cost-effectiveness ratios for all-comers, patients with proficient mismatch repair tumors, and deficient mismatch repair tumors. Deterministic and probabilistic sensitivity analyses were conducted. RESULTS: Pembrolizumab plus lenvatinib is a cost-effective treatment when compared with chemotherapy, with estimated deterministic and probabilistic incremental cost-effectiveness ratios of SEK 795,712 and 819,757 per QALY gained. Pembrolizumab plus lenvatinib was associated with a large incremental QALY and life-year gain per person versus chemotherapy over the model time horizon (1.49 and 1.76). LIMITATIONS: Time-to-event data were incomplete and semiparametric and parametric curves were utilized for lifetime extrapolation. Willingness-to-pay thresholds, costs, and utility weights vary by country, which would vary the treatment's cost effectiveness in different countries. CONCLUSIONS: This partitioned survival analysis suggests that pembrolizumab plus lenvatinib is cost effective compared with chemotherapy in Sweden for women with advanced or recurrent endometrial carcinoma following previous systemic therapy. Results were robust to mismatch repair status and to changes in parameters/assumptions.

Atractylenolide II Suppresses Glycolysis and Induces Apoptosis by Blocking the PADI3-ERK Signaling Pathway in Endometrial Cancer Cells.

Atractylenolide II (AT-II), the major bioactive compound of Atractylodes macrocephala, exhibits anti-cancer activity against many types of tumors, but the roles and the potential mechanisms in endometrial cancer remain unclear. In the present study, AT-II treatment was found to significantly suppress RL95-2 and AN3CA cell proliferation and glycolysis, and induced their apoptosis by inactivating the ERK signaling pathway, accompanied by the changing expression of the glycolytic key enzymes and apoptotic-related proteins. Peptidyl arginine deiminase 3 (PADI3), as the candidate target gene of AT-II, was highly expressed in the endometrial cancer tissues and associated with a poor prognosis according to bioinformatics analysis. PADI3 knockdown inhibited proliferation and glycolysis in endometrial cancer cells and induced cell apoptosis. Furthermore, AT-II negatively regulated the expression of PADI3, and PADI3 overexpression reversed the effects of AT-II on endometrial cancer cells. Our findings suggested that the anti-cancer function of AT-II is associated with the suppression of glycolysis and induction of apoptosis by blocking the PADI3-ERK signaling pathway. Thus, AT-II represents a novel therapeutic target for endometrial cancer and targeting AT-II may serve as a potential strategy for the clinical therapy of endometrial cancer.

[The long-term efficacy of metformin in megestrol acetate-based fertility-sparing treatment for patients with endometrial atypical hyperplasia and endometrioid endometrial cancer].

Objective: To assess the long-term efficacy of metformin in megestrol acetate (MA)-based fertility-sparing treatment for patients with endometrial atypical hyperplasia (EAH) and endometrioid endometrial cancer (EEC). Methods: The randomized controlled trail study was conducted from October 2013 to October 2017 in the Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China. Patients with EAH or EEC were firstly stratified according to pathology, and randomized to receive MA (160 mg orally, daily) plus metformin (500 mg orally, three times a day) or MA (160 mg orally, daily). Baseline data between two groups of patients were compared. Estimates of time to complete remission (CR) and recurrence-free survival (RFS) were calculated using the Kaplan-Meier method. Cox proportional-hazards regression model was used to estimate hazard ratios (HR) of related factors for recurrence-free survival. Quantitative data were represented by M (Q1, Q3). Results: A total of 150 patients were included, and 76 patients were allocated to receive MA plus metformin with the age of 32.5 (28.0, 36.0), while 74 patients received MA alone with the age of 32.0 (28.0, 36.0). By the end of follow-up period, 96.7% (n=145) of patients achieved complete remission, with a median follow-up time of 57.7 (26.7, 70.5) months. The median CR time for the MA plus metformin group and the MA alone group were 6.3 (3.5, 8.3) months and 6.8 (4.0, 9.3) months, respectively (P=0.193), with 2-year cumulative CR rate of 98.6% and 98.5%, respectively (P=0.879). The median time of RFS was 28.1 (12.5, 57.3) months for the MA plus metformin group and 33.3 (14.1, 62.5) months for the MA alone group (P=0.213), with a cumulative RFS rate of 61.9% and 65.8%, respectively (P=0.560). In the subgroup of non-obese (body mass index<28 kg/m2) patients with EAH, the median RFS times were 25.7 (7.6, 60.3) months and 47.3 (17.5, 64.8) months for the MA plus metformin group and the MA alone group, respectively (P=0.033), with a cumulative RFS rate of 57.5% and 80.6%, respectively (P=0.029). According to Cox proportional hazards regression analysis, undergoing assisted reproductive treatment (HR=2.358, 95%CI: 1.069-5.204, P=0.034) was identified as an independent risk factor for recurrence-free survival after complete remission of endometrial lesions. Conclusion: The long-term follow-up outcome indicates that there is no significant difference in CR time and RFS time between MA plus metformin therapy and MA alone therapy for patients with EAH or EEC.

Linoleic acid exhibits anti-proliferative and anti-invasive activities in endometrial cancer cells and a transgenic model of endometrial cancer.

Emerging evidence has provided considerable insights into the integral function of reprogramming fatty acid metabolism in the carcinogenesis and progression of endometrial cancer. Linoleic acid, an essential fatty acid with the highest consumption in the Western diet regimen, has shown pro-tumorigenic or anti-tumorigenic effects on tumor cell growth and invasion in multiple types of cancer. However, the biological role of linoleic acid in endometrial cancer remains unclear. In the present study, we aimed to investigate the functional impact of linoleic acid on cell proliferation, invasion, and tumor growth in endometrial cancer cells and in a transgenic mouse model of endometrial cancer. The results showed that Linoleic acid significantly inhibited the proliferation of endometrial cancer cells in a dose-dependent manner. The treatment of HEC-1A and KLE cells with linoleic acid effectively increased intracellular reactive oxygen species (ROS) production, decreased mitochondrial membrane potential, caused cell cycle G1 arrest, and induced intrinsic and extrinsic apoptosis pathways. The anti-invasive ability of linoleic acid was found to be associated with the epithelial-mesenchymal transition process in both cell lines, including the decreased expression of N-cadherin, snail, and vimentin. Furthermore, treatment of Lkb1fl/flp53fl/fl transgenic mice with linoleic acid for four weeks significantly reduced the growth of endometrial tumors and decreased the expression of VEGF, vimentin, Ki67, and cyclin D1 in tumor tissues. Our findings demonstrate that linoleic acid exhibits anti-proliferative and anti-invasive activities in endometrial cancer cell lines and the Lkb1fl/flp53fl/fl mouse model of endometrial cancer, thus providing a pre-clinical basis for future dietary interventions with linoleic acid in endometrial cancer.

Levels of depression and self-esteem in women with cancer of the endometrium and cervix receiving chemotherapy treatment in Türkiye.

OBJECTIVE: Endometrium and cervical cancer is a common and important health problem that affects women in many physical, emotional and psychological aspects. This study aimed to determine the levels of depression and self-esteem in women with endometrial and cervical cancer receiving chemotherapy, determine the factors affecting them, and examine the relationship between the levels of depression and self-esteem. METHODS: This descriptive and cross-sectional study was conducted with 158 women who came to the gynecology-oncology policlinic and chemotherapy unit of a training and research hospital in Izmir, western Türkiye, between April 2022 and April 2023. Data were collected with the "Descriptive Information Form", "Beck Depression Inventory" and "Rosenberg Self-Esteem Scale". Descriptive and inferential statistics were performed to analyse the association between the study variables. RESULTS: In this study, 52.5% of women were diagnosed with endometrial cancer and 47.5% with cervical cancer. Beck Depression Inventory mean total score was 11.28 ±â€¯6.35, and 20.3% of them were at risk of depression (BDI ≥ 17). Rosenberg Self-Esteem Scale mean total score was 21.06 ±â€¯3.85, and 97.5% of them had high self-esteem. There was a statistically significant and strong negative correlation between the mean total scores of the Beck Depression Inventory and Rosenberg Self-Esteem Scale (r = 0.723; p < 0.05). It was determined that an increase in the Rosenberg Self-Esteem Scale mean total score by 1 unit decreased the Beck Depression Inventory mean total score by 1.2 units and was responsible for 52% of the variance (B = -1.192; R2 = 0.523). CONCLUSION: It was determined that one-fifth of women experienced moderate/severe depression and the majority of them had high self-esteem. The increase in women's depression levels decreased their self-esteem. Health professionals and oncology nurses should perform screenings to determine the depression and self-esteem levels of women with endometrial and cervical cancer and provide necessary education, counseling, and care to women.

Adding immunotherapy to first-line treatment of advanced and metastatic endometrial cancer.

BACKGROUND: Immunotherapy has transformed the endometrial cancer treatment landscape, particularly for those exhibiting mismatch repair deficiency [MMRd/microsatellite instability-hypermutated (MSI-H)]. A growing body of evidence supports the integration of immunotherapy with chemotherapy as a first-line treatment strategy. Recently, findings from ongoing trials such as RUBY (NCT03981796), NRG-GY018 (NCT03914612), AtTEnd (NCT03603184), and DUO-E (NCT04269200) have been disclosed. MATERIALS AND METHODS: This paper constitutes a review and meta-analysis of phase III trials investigating the role of immunotherapy in the first-line setting for advanced or recurrent endometrial cancer. RESULTS: The pooled data from 2320 patients across these trials substantiate the adoption of chemotherapy alongside immunotherapy, revealing a significant improvement in progression-free survival compared to chemotherapy alone [hazard ratio (HR) 0.70, 95% confidence interval (CI) 0.62-0.79] across all patient groups. Progression-free survival benefits are more pronounced in MMRd/MSI-H tumors (n = 563; HR 0.33, 95% CI 0.23-0.43). This benefit, albeit less robust, persists in the MMR-proficient/microsatellite stable group (n = 1757; HR 0.74, 95% CI 0.60-0.91). Pooled data further indicate that chemotherapy plus immunotherapy enhances overall survival compared to chemotherapy alone in all patients (HR 0.75, 95% CI 0.63-0.89). However, overall survival data maturity remains low. CONCLUSIONS: The incorporation of immunotherapy into the initial treatment for advanced and metastatic endometrial cancer brings about a substantial improvement in oncologic outcomes, especially within the MMRd/MSI-H subset. This specific subgroup is currently a focal point of investigation for evaluating the potential of chemotherapy-free regimens. Ongoing exploratory analyses aim to identify non-responding patients eligible for inclusion in clinical trials.

Targeting GRP75 with a Chlorpromazine Derivative Inhibits Endometrial Cancer Progression Through GRP75-IP3R-Ca2+-AMPK Axis.

Tumors often overexpress glucose-regulated proteins, and agents that interfere with the production or activity of these proteins may represent novel cancer treatments. The chlorpromazine derivative JX57 exhibits promising effects against endometrial cancer with minimal extrapyramidal side effects; however, its mechanisms of action are currently unknown. Here, glucose-regulated protein 75 kD (GRP75) is identified as a direct target of JX57 using activity-based protein profiling and loss-of-function experiments. The findings show that GRP75 is necessary for the biological activity of JX57, as JX57 exhibits moderate anticancer properties in GRP75-deficient cancer cells, both in vitro and in vivo. High GRP75 expression is correlated with poor differentiation and poor survival in patients with endometrial cancer, whereas the knockdown of GRP75 can significantly suppress tumor growth. Mechanistically, the direct binding of JX57 to GRP75 impairs the structure of the mitochondria-associated endoplasmic reticulum membrane and disrupts the endoplasmic reticulum-mitochondrial calcium homeostasis, resulting in a mitochondrial energy crisis and AMP-activated protein kinase activation. Taken together, these findings highlight GRP75 as a potential prognostic biomarker and direct therapeutic target in endometrial cancer and suggest that the chlorpromazine derivative JX57 can potentially be a new therapeutic option for endometrial cancer.