Therapy For Endometrial Cancer Research Articles

Managing the Adverse Events Associated with Pembrolizumab and Lenvatinib Therapy in Endometrial Cancer

Endometrial cancer (EC) is the most common gynaecological cancer. The combination of lenvatinib and pembrolizumab has exhibited efficacy as the second line treatment for advanced EC, with a significant benefit in terms of progression free survival (PFS) and overall survival, but the adverse events (AE) profile is complex. AEs associated with the treatment may represent a limitation to this combination. Here, we report the case of a 38-year-old female patient diagnosed with stage IV EC elsewhere, whose disease progressed after the first line of treatment and was referred to a specialised cacncer centre in Muscat, Oman, in 2021. We treated her with the combination of lenvatinib and pembrolizumab. During the course of the treatment, she developed hand-foot syndrome grade III and hypothyroidism grade II. The AEs were managed with supportive medications, dose interruptions, dose reductions and multidisciplinary care, which allowed the continuation of the treatment. The patient achieved a good partial response and an ongoing PFS of more than 12 months. Keywords: Cancer; Endometrial Cancer; Lenvatinib; Pembrolizumab; Adverse Drug Events; Hand-Foot Syndrome; Hypothyroidism; Oman.

IGF2BP2-modified circular RNA circCHD7 promotes endometrial cancer progression via stabilizing PDGFRB and activating JAK/STAT signaling pathway.

Circular RNAs (circRNAs) represent a class of covalently closed, single-stranded RNAs and have been linked to cancer progression. N6-methyladenosine (m6A) methylation is a ubiquitous RNA modification in cancer cells. Increasing evidence suggests that m6A can mediate the effects of circRNAs in cancer biology. In contrast, the post-transcriptional systems of m6A and circRNA in the progression of endometrial cancer (EC) remain obscure. The current study identified a novel circRNA with m6A modification, hsa_circ_0084582 (circCHD7), which was upregulated in EC tissues. Functionally, circCHD7 was found to promote the proliferation of EC cells. Mechanistically, circCHD7 interacted with insulin-like growth factor 2 mRNA-binding protein (IGF2BP2) to amplify its enrichment. Moreover, circCHD7 increased the mRNA stability of platelet-derived growth factor receptor beta (PDGFRB) in an m6A-dependent manner, thereby enhancing its expression. In addition, the circCHD7/IGF2BP2/PDGFRB axis activated the JAK/STAT signaling pathway and promoted EC cell proliferation. In conclusion, these findings provide new insights into the regulation of circRNA-mediated m6A modification, and the new "circCHD7-PDGFRB" model of regulation offers new perspectives on circCHD7 as a potential target for EC therapy.

Tumor microenvironment parameters as a predictor of the duration of clinical effectiveness of immunotargeted therapy in advanced or metastatic endometrial cancer: A pilot multicenter observational study

Background. The inclusion of lenvatinib in the immunotherapy regimen for patients with MSS/pMMR endometrial cancer (EC) is due to its ability to modulate the tumor microenvironment, which allows the use of pembrolizumab in low-immunogenic tumors. However, only 30 % of patients with advanced or metastatic EC have a clinical response when treated with pembrolizumab and lenvatinib. In this regard, there is an obvious need to identify biomarkers that allow accurate selection of candidates for this type of therapy.Aim. To determine the predictive value of subpopulations of lymphocytes and macrophages, their expression of PD-1, expression of estrogen receptors, as well as vessel density in immunotargeted therapy for advanced or metastatic EC.Materials and methods. An open-label non-randomized observational association study was performed, involving a total of 22 patients with advanced or metastatic MSS/pMMR EC treated with pembrolizumab and lenvatinib. Duration of clinical effectiveness was used as a parameter to stratify patients. Using TSA-associated multiplex immunofluorescence, the proportions of CD8+ T lymphocytes, CD20+ B lymphocytes, FoxP3+ T regulatory lymphocytes and CD163+macrophages in tumor samples before the start of immunotargeted therapy were analyzed.Results. Three microenvironmental parameters were found to be associated with duration of clinical efficacy: the proportion of CD20+ B cells, the proportion of FoxP3+ T regulatory lymphocytes, and the ratio of CD8+/CD20+ lymphocytes in the tumor microenvironment. However, the CD8+/CD20+ lymphocyte ratio had the greatest predictive value; a value below 3.219 was associated with long clinical efficacy in patients with advanced or metastatic EC.Conclusion. The ratio of cytotoxic and B-lymphocytes in the microenvironment is a reliable predictor marker of the duration of the period of clinical effectiveness of immunotargeting therapy in advanced or metastatic EC.

Old Issues and New Perspectives on Endometrial Cancer Therapy: How Molecular Characteristics Are Changing the Therapeutic Pathway.

The Cancer Genome Atlas (TCGA) has radically changed the history of endometrial cancer by outlining a new classification, based on its molecular characteristics. In the field of oncology, we are approaching the new era of molecular biology, particularly regarding endometrial cancer, with the increasing importance of targeted therapy. This paper is a review of phase III randomized controlled trials published in English between January 2019 and December 2023, comparing drugs of interest with standard adjuvant treatment and molecular subtypes in endometrial cancer. The use of immunotherapy alone or in combination with chemotherapy as therapy in patients with recurrent or advanced primary or metastatic endometrial cancer significantly improves the prognosis of these patients. The results show greater efficacy of all proposed treatments for mismatch repair deficiency (dMMR/MSI-H) patients compared to mismatch repair proficiency (pMMR) patients. Progression-free survival (PFS) and overall survival (OS) are better in dMMR patients in all studies analysed. Immunotherapy has the potential to revolutionize the gynaecological cancer treatment landscape, offering a new pathway and new hope for endometrial cancer patients, improving their outcomes in the future. Given the exciting results obtained in dMMR/MSI-H patients, MMR status should be investigated in every patient with advanced endometrial cancer at the time of diagnosis.

MITO END-3: efficacy of avelumab immunotherapy according to molecular profiling in first-line endometrial cancer therapy

Immunotherapy combined with chemotherapy significantly improves progression-free survival compared to first-line chemotherapy alone in advanced endometrial cancer, with a much larger effect size in microsatellite-instability high (MSI-H) cases. New biomarkers might help to select patients that may have benefit among those with a microsatellite-stable (MSS) tumor. In a pre-planned translational analysis of the MITO END-3 trial, we assessed the significance of genomic abnormalities in patients randomized to standard carboplatin/paclitaxel without or with avelumab. Out of 125 randomized patients, 109 had samples eligible for next-generation sequencing (NGS) analysis, and 102 had MSI tested. According to The Cancer Genome Atlas (TCGA), there were 29 cases MSI-H, 26 MSS TP53 wild-type (wt), 47 MSS TP53 mutated (mut), and one case with POLE mutation. Four mutated genes were present in more than 30% of cases: TP53, PIK3CA, ARID1A, and PTEN. Eleven patients (10%) had a BRCA1/2 mutation (five in MSI-H and six in MSS). High TMB (≥10 Muts/Mb) was observed in all MSI-H patients, in four out of 47 MSS/TP53 mut, and no case in the MSS/TP53 wt category. The effect of avelumab on progression-free survival significantly varied according to TCGA categories, being favorable in MSI-H and worst in MSS/TP53 mut (P interaction=0.003); a similar non-significant trend was seen in survival analysis. ARID1A and PTEN also showed a statistically significant interaction with treatment effect, which was better in the presence of the mutation (ARID1A P interaction=0.01; PTEN P interaction=0.002). The MITO END-3 trial results suggest that TP53 mutation is associated with a poor effect of avelumab, while mutations of PTEN and ARID1A are related to a positive effect of the drug in patients with advanced endometrial cancer.

Radiation Therapy With or Without Cisplatin for Local Recurrences of Endometrial Cancer: Results From an NRG Oncology/GOG Prospective Randomized Multicenter Clinical Trial.

Pelvic recurrence is a frequent pattern of relapse for women with endometrial cancer. A randomized trial compared progression-free survival (PFS) after treatment with radiation therapy alone as compared with concurrent chemotherapy. Between February 2008 and August 2020, 165 patients were randomly assigned 1:1 to receive either radiation treatment alone or a combination of chemotherapy and radiation treatment. The primary objective of this study was to determine whether chemoradiation therapy was more effective than radiation therapy alone at improving PFS. The majority of patients had low-grade (1 or 2) endometrioid histology (82%) and recurrences confined to the vagina (86%). External beam with either the three-dimensional or intensity modulated radiation treatment technique was followed by a boost delivered with brachytherapy or external beam. Patients randomly assigned to receive chemotherapy were treated with once weekly cisplatin (40 mg/m2). Rates of acute toxicity were higher in patients treated with chemoradiation as compared with radiation treatment alone. Median PFS was longer for patients treated with radiation therapy alone as compared with chemotherapy and radiation (median PFS was not reached for RT v 73 months for chemoradiation, hazard ratio of 1.25 (95% CI, 0.75 to 2.07). At 3 years, 73% of patients treated definitively with radiation and 62% of patients treated with chemoradiation were alive and free of disease progression. Excellent outcomes can be achieved for women with localized recurrences of endometrial cancer when treated with radiation therapy. The addition of chemotherapy does not improve PFS for patients treated with definitive radiation therapy for recurrent endometrial cancer and increases acute toxicity. Patients with low-grade and vaginal recurrences who constituted the majority of those enrolled are best treated with radiation therapy alone.

ERBB2 Targeting Reveals a Significant Suppression of Tumorigenesis in Murine Endometrial Cancer with Pten Mutation.

Endometrial cancer is the most common gynecologic malignancy. PTEN is a negative regulator of PI3K signaling and is deficient in > 50% of primary human endometrial cancer. Amplification of ERBB2 promotes tumorigenesis and pathogenesis of several human cancers. However, the effect of ERBB2 targeting has not been studied in endometrial cancer with PTEN mutations. The murine model Pgrcre/+Erbb2f/fPtenf/f (Erbb2d/d Ptend/d) was developed to evaluate the effect of ERBB2 targeted therapy in endometrial cancer with PTEN deficiency. Histopathological and molecular analysis was performed for Ptend/d and Erbb2d/dPtend/d mice. Histopathological analysis revealed that Erbb2d/dPtend/d mice significantly reduced development and progression of endometrial cancer compared to Ptend/d mice. Furthermore, percentage of proliferative cells in Erbb2d/dPtend/d mice revealed anti-tumorigenic effect of Erbb2 ablation compared to Ptend/d mice. Our results demonstrate that Erbb2 ablation reveals a significant suppression of tumorigenesis on endometrial cancer of Ptend/d mice. Our results suggest that Erbb2 functions as an oncogene in endometrial cancer of Ptend/d mice implying that Erbb2 targeting can be used as an effective therapeutic approach for treatment of endometrial cancer with PTEN deficiency to hinder cancer development.

"Evaluation of Multimodality Imaging Based Vaginal Cuff Boost with Stereotactic Body Radiation Therapy (SBRT) for Endometrial Cancer: An Original Article"

"Evaluation of Multimodality Imaging Based Vaginal Cuff Boost with Stereotactic Body Radiation Therapy (SBRT) for Endometrial Cancer: An Original Article"

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.

Daily Online Adaptive Radiation Therapy of Postoperative Endometrial and Cervical Cancer With PTV Margin Reduction to 5 mm: Dosimetric Outcomes, Acute Toxicity, and First Clinical Experience

PurposeThis study evaluated the first clinical implementation of daily iterative cone-beam computed tomography (iCBCT)-guided online adaptive radiotherapy (oART) in the postoperative treatment of endometrial and cervical cancer. Methods and MaterialsSeventeen consecutive patients treated with daily iCBCT-guided oART were enrolled in this prospective study, with a reduced uniform three-dimensional PTV margin of 5 mm. Treatment plans were designed to deliver 45 or 50.4 Gy in 1.8 Gy daily fractions to PTV. Pre- and posttreatment ultrasound and iCBCT scans were performed to record intrafractional bladder and rectal volume changes. The accuracy of contouring, oART procedure time, dosimetric outcomes and acute toxicity were evaluated. ResultsThe average time from first iCBCT acquisition to completion of treatment was 22 min and 26 s. During this period, bladder volume increased by 44 cm3 using iCBCT contouring, while rectal volume remained stable (62.9 cm3 pretreatment vs. 61.9 cm3 posttreatment). A total of 91.6% of influencers and 88.1% of CTVs required no or minor edits. The adapted plan was selected in all (434) fractions and significantly improved the dosimetry coverage for CTV and PTV, especially the vaginal PTV coverage by nearly 7% (p<0.05). The adapted bladder Dmean was 104.61 cGy, and the rectum Dmean was 123.67 cGy, significantly lower than the scheduled plan of 108.24 and 128.19 cGy, respectively. The bone marrow, femur head left and right dosimetry were also improved with adaptation. Grade 2 acute gastrointestinal and genitourinary toxicities were 24% and 0, respectively. There was a Grade 3 acute toxicity of decreased white blood cell count in one patient. ConclusionsDaily oART was associated with favourable dosimetry improvement and low acute toxicity, supporting its safety and efficacy for postoperative treatment of endometrial and cervical cancer. These results need to be validated in a larger prospective randomized controlled cohort.

Treatment of Chronic Endometritis with Vague Symptoms in Patients with Endometrial Hyperplasia

Aim. To develop new therapeutic approaches for chronic endometritis with vague symptoms, which is frequently diagnosed in patients with endometrial hyperplasia.Materials and Methods. We collected the material from uterine scrapings in patients (age 25-63 years) with endometrial hyperplasia (diagnosed by ultrasound examination) and abnormal uterine bleeding which occurred during hysteroscopic dilation and curettage. Among the exclusion criteria were intraepithelial neoplasia and atypical endometrial hyperplasia, cancer, systemic inflammation, and hormonal therapy. To verify the diagnosis, we employed immunohistochemistry, digital slide scanning, and morphometry.Results. This study confirmed the value of immunohistochemical diagnosis underlying the pathogenetic therapy of endometrial hyperplasia using non-steroidal anti-inflammatory drugs. Inflammatory markers indicating the distribution and quantitative alterations in cell populations had the highest diagnostic value.Conclusion. We developed a molecularly oriented algorithm for the treatment of patients with endometrial hyperplasia. This algorithm improves existing preventive, diagnostic and therapeutic approaches using immunohistochemical techniques. Such molecular testing can help in making correct therapeutic decisions.

Accuracy of endometrial sampling in the diagnosis of endometrial cancer: a multicenter retrospective analysis of the JAGO-NOGGO

BackgroundAccurate preoperative molecular and histological risk stratification is essential for effective treatment planning in endometrial cancer. However, inconsistencies between pre- and postoperative tumor histology have been reported in previous studies. To address this issue and identify risk factors related to inaccurate histologic diagnosis after preoperative endometrial evaluation, we conducted this retrospective analysis.MethodsWe conducted a retrospective analysis involving 375 patients treated for primary endometrial cancer in five different gynaecological departments in Germany. Histological assessments of curettage and hysterectomy specimens were collected and evaluated.ResultsPreoperative histologic subtype was confirmed in 89.5% of cases and preoperative tumor grading in 75.2% of cases. Higher rates of histologic subtype variations (36.84%) were observed for non-endometrioid carcinomas. Non-endometrioid (OR 4.41) histology and high-grade (OR 8.37) carcinomas were identified as predictors of diverging histologic subtypes, while intermediate (OR 5.04) and high grading (OR 3.94) predicted diverging tumor grading.ConclusionWhen planning therapy for endometrial cancer, the limited accuracy of endometrial sampling, especially in case of non-endometrioid histology or high tumor grading, should be carefully considered.

Abstract B016: Novel curcumin analogues as therapies for endometrial cancer with TP53 mutations

Abstract The protein p53 is designated as the guardian of the genome because it is the principal tumor suppressor and functions to surveil the genome, enforce cell cycle checkpoints, and trigger apoptosis when genomic instability is beyond repair. Mutations in TP53 are found in &amp;gt;50% of human tumors and in 25% of the deadliest endometrial malignancies. Yet, few studies have targeted the mutant protein to restore its wild type (WT) tumor suppressor functions. Curcumin, a turmeric derivative, has been shown to help return WT function to mutant p53. However, curcumin is not bioavailable to most of the body because of its water insolubility, hydrophobic nature and rapid metabolization. Our laboratory is testing novel, more bioavailable analogs of curcumin including HO-3867 and AKT-100. In these studies, we tested these agents in preclinical models of serous endometrial cancer to assess their effects on cell growth and p53-dependent signaling. We used CyQUANT cell proliferation assay to identify IC50 values for HO-3867 and AKT-100 in ECC-1 and KLE endometrial cancer cell lines. We performed RNA sequencing to elucidate mechanisms of action and verified p53 expression changes via Western blotting. IC50 values ranged from 100 nanomolar (AKT-100) to low micromolar (HO-3867). RNA sequencing data revealed the re-enforcement of cell cycle checkpoints including the upregulation of CDKN1A (p21) and GADD45 (Gadd45). Proliferative signaling downstream of ATM, an important protein kinase stimulating cell growth, was downregulated by both agents. Western blotting confirmed the classic negative feedback loop of p53, where total p53 levels decreased after drug treatment. Taken together, our findings show that AKT-100 and HO-3867 are able to restore WT tumor suppressor function in otherwise oncogenic mutant p53 by reducing cell replication and promoting apoptosis. Thus, curcumin analogues such as AKT-100 and HO-3867 show promise in the treatment of a subset of endometrial tumors expressing mutant p53 by returning WT p53 functionality, and future studies will move to in vivo analyses of curcumin analogue function. Citation Format: Kimberly K. Leslie, Alex Goss, Jamie Padilla, Lane E. Smith. Novel curcumin analogues as therapies for endometrial cancer with TP53 mutations [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr B016.

Impact of artificial intelligence on the diagnosis, treatment and prognosis of endometrial cancer.

Endometrial cancer is one of the most prevalent tumours in females and holds an 83% survival rate within 5 years of diagnosis. Hypoestrogenism is a major risk factor for the development of endometrial carcinoma (EC) therefore two major types are derived, type 1 being oestrogen-dependent and type 2 being oestrogen independent. Surgery, chemotherapeutic drugs, and radiation therapy are only a few of the treatment options for EC. Treatment of gynaecologic malignancies greatly depends on diagnosis or prognostic prediction. Diagnostic imaging data and clinical course prediction are the two core pillars of artificial intelligence (AI) applications. One of the most popular imaging techniques for spotting preoperative endometrial cancer is MRI, although this technique can only produce qualitative data. When used to classify patients, AI improves the effectiveness of visual feature extraction. In general, AI has the potential to enhance the precision and effectiveness of endometrial cancer diagnosis and therapy. This review aims to highlight the current status of applications of AI in endometrial cancer and provide a comprehensive understanding of how recent advancements in AI have assisted clinicians in making better diagnosis and improving prognosis of endometrial cancer. Still, additional study is required to comprehend its strengths and limits fully.

Cost effectiveness of immunotherapy combination therapies for endometrial cancer

Over the past five years (2019–2023), several new targeted therapies and immunotherapy has been approved in treating relapsed cervical, ovarian, and endometrial cancers. Concurrently, there has been growing recognition of financial toxicity associated with cancer care during this time period. As such, we reviewed FDA approvals from 2019 to 2013 and identified the following approvals in gynecologic oncology: pembrolizumab plus lenvatinib, pembrolizumab for recurrent endometrial cancer that is MSI-H/dMMR, tisotumab vedotin, dostarlimab as single-agent therapy, and dostarlimab plus chemotherapy. We focused on approvals for endometrial cancer, and conducted a cost-effectiveness analysis for combination options approved in treating recurrent or advanced endometrial cancer (i.e. pembrolizumab plus lenvatinib versus placebo; dostarlimab plus chemotherapy versus placebo), and found neither regimen was cost-effective at a willingness-to-pay of $100,000 per Equal Value of Life Years Gained (evLYG). While these costs may not necessarily be translated to an individual patient, these costs are absorbed by healthcare systems and insurance providers on a larger scale with downstream effects on individuals contributing to healthcare costs a whole.

LATS1/2 loss promote tumor immune evasion in endometrial cancer through downregulating MHC-I expression.

LATS1/2 are frequently mutated and down-regulated in endometrial cancer (EC), but the contributions of LATS1/2 in EC progression remains unclear. Impaired antigen presentation due to mutations or downregulation of the major histocompatibility complex class I (MHC-I) has been implicated in tumor immune evasion. Herein, we elucidate the oncogenic role that dysregulation of LATS1/2 in EC leads to immune evasion through the down-regulation of MHC-I. The mutation and expression as well as the clinical significance of LATS1/2 in EC was assessed in the TCGA cohort and our sample cohort. CRISPR-Cas9 was used to construct knockout cell lines of LATS1/2 in EC. Differentially expressed genes were analyzed by RNA-seq.The interaction between LATS1/2 and STAT1 was verified using co-immunoprecipitation and GST pull-down assays. Mass spectrometry, in vitro kinase assays, ChIP-qPCR, flow cytometry, immunohistochemistry, immunofluorescence and confocal microscopy were performed to investigate the regulation of LATS1/2 on MHC-I through interaction with and phosphorylate STAT1. The killing effect of activated PBMCs on EC cells were used to monitor anti-tumor activity. Here, we demonstrate that LATS1/2 are frequently mutated and down-regulated in EC. Moreover, LATS1/2 loss was found to be associated with a significant down-regulation of MHC-I, independently of the Hippo-YAP pathway. Instead, LATS1/2 were found to directly interact with and phosphorylate STAT1 at Ser727, a crucial transcription factor for MHC-I upregulation in response to interferon-gamma (IFN-γ) signaling, to promote STAT1 accumulating and moving into the nucleus to enhance the transcriptional activation of IRF1/NLRC5 on MHC-I. Additionally, the loss of LATS1/2 was observed to confer increased resistance of EC cells to immune cell-mediated killing and this resistance could be reversed by over-expression of MHC-I. Our findings indicate that dysregulation of LATS1/2 in EC leads to immune evasion through the down-regulation of MHC-I, leading to the suppression of infiltrating activated CD8 + T cells and highlight the importance of LATS1/2 in IFN-γ signaling-mediated tumor immune response, suggesting that LATS1/2 is a promising target for immune checkpoint blockade therapy in EC.

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.

Metabolism pathway-based subtyping in endometrial cancer: An integrated study by multi-omics analysis and machine learning algorithms

Endometrial cancer (EC), the second most common malignancy in the female reproductive system, has garnered increasing attention for its genomic heterogeneity, but understanding of its metabolic characteristics is still poor. We explored metabolic dysfunctions in EC through comprehensive multi-omics analysis (RNA-seq datasets from The Cancer Genome Atlas (TCGA), Cancer Cell Line Encyclopedia (CCLE), and GEO datasets; the Clinical Proteomic Tumor Analysis Consortium (CPTAC) proteomics; CCLE metabolomics) to develop useful molecular targets for precision therapy. Unsupervised consensus clustering was performed to categorize EC patients into three metabolism-pathways-based subgroups (MPS). These MPS subgroups had distinct clinical prognoses, transcriptomic and genomic alterations, immune microenvironment landscape, and unique patterns of chemotherapy sensitivity. Moreover, the MPS2 subgroup has a better response to immunotherapy. Finally, three machine learning algorithms (LASSO, random forest, and stepwise multivariate Cox regression) were used for developing a prognostic “Metagene” signature based on metabolic molecules. Thus, a thirteen-hub-gene-based classifier was constructed to predict patients’ MPS subtype offering a more accessible and practical approach. This metabolism-based classification system can potentially enhance prognostic predictions and guide clinical strategies for immunotherapy and metabolism-targeted therapy in EC.

EphA2- and HDAC-Targeted Combination Therapy in Endometrial Cancer.

Endometrial cancer is the most frequent malignant tumor of the female reproductive tract but lacks effective therapy. EphA2, a receptor tyrosine kinase, is overexpressed by various cancers including endometrial cancer and is associated with poor clinical outcomes. In preclinical models, EphA2-targeted drugs had modest efficacy. To discover potential synergistic partners for EphA2-targeted drugs, we performed a high-throughput drug screen and identified panobinostat, a histone deacetylase inhibitor, as a candidate. We hypothesized that combination therapy with an EphA2 inhibitor and panobinostat leads to synergistic cell death. Indeed, we found that the combination enhanced DNA damage, increased apoptosis, and decreased clonogenic survival in Ishikawa and Hec1A endometrial cancer cells and significantly reduced tumor burden in mouse models of endometrial carcinoma. Upon RNA sequencing, the combination was associated with downregulation of cell survival pathways, including senescence, cyclins, and cell cycle regulators. The Axl-PI3K-Akt-mTOR pathway was also decreased by combination therapy. Together, our results highlight EphA2 and histone deacetylase as promising therapeutic targets for endometrial cancer.

Combination of pembrolizumab and lenvatinib in second-line therapy for MSS/pMMR advanced endometrial cancer: literature review and a case report

Despite the existing standard treatments for endometrial cancer, the prognosis for these patients remained poor until recently. None of currently available cytostatics ensured long-term disease control and long-term survival of patients receiving standard platinum-based therapy. Poor treatment outcomes in patients with advanced endometrial cancer necessitated changes in therapeutic approaches and development of more effective treatment regimens. Better understanding of carcinogenesis mechanisms, emergence of a new molecular classification of endometrial cancer, and implementation of tailored treatment approaches based on tumor types led to a significant breakthrough in the treatment of advanced endometrial cancer. Currently, the most effective second-line therapy for endometrial cancer with high level microsatellite instability (MSI-h) or deficient mismatch repair system (dMMR) (25 % of cases), and no indications for surgery is pembrolizumab monotherapy. Most of cancers (about 75 %) are represented by microsatellite-stable and mismatch repair proficient tumors (MSS/рMMR). Patients with such tumors demonstrating disease progression after systemic therapy should receive a combinations of the immune checkpoint inhibitor pembrolizumab and the multi-targeted tyrosine kinase inhibitor lenvatinib. In this article, we review relevant literature and report a case of successful treatment of MSS/pMMR advanced endometrial cancer with a combination of pembrolizumab and lenvatinib as a second-line therapy (after disease progression in response to platinum-containing first-line chemotherapy), which ensured long-term disease control.