Search Results (501)

Ovarian cancer (OC) is a particularly lethal gynecological malignancy with few treatment options due to its late-stage diagnosis, extensive genetic heterogeneity, and frequent development of resistance to existing therapies. Immunotherapy has revolutionized the management and clinical outcome of numerous solid tumors, but its clinical benefit for OC has been limited, in part due to an extremely immunosuppressive tumor microenvironment (TME) and diverse, overlapping immune evasion mechanisms. In this review, we present a comprehensive and timely synthesis of next-generation immunotherapeutic approaches for ovarian cancer, emphasizing strategies that overcome the immunosuppressive tumor microenvironment and improve clinical responsiveness. We describe the emerging molecular mechanisms of immune evasion in OC, including altered antigen presentation, inhibition of T-cell activation (e.g., via immunological checkpoints, metabolic reprogramming), polarization of tumor-associated macrophages (TAMs), and dysfunction of natural killer (NK) cells. We also critically examine several emerging therapeutic approaches, including combination immune checkpoint blockade (ICB), bispecific T-cell engagers (BiTEs), neoantigen-based vaccines, chimeric antigen receptor (CAR)-T- and CAR-NK-cell therapies, oncolytic viruses (OVs), and nanoparticle-mediated immunomodulation. In addition, we highlight recent advances in tumor microenvironment–targeted therapies for ovarian cancer, focusing on strategies that modulate non-lymphoid components such as cancer-associated fibroblasts (CAFs), hypoxia-driven signaling, and the PI3K/AKT/mTOR axis to enhance antitumor immune responsiveness. Finally, we discuss how predictive biomarkers, multi-omics systems, and patient-derived organoid models are accelerating the development and deployment of precision immunotherapies for OC. We would like to highlight the translational promise of next-generation immunotherapies and identify novel molecular targets that may be leveraged to achieve durable responses in OC. Full article

Background/Objectives: Ovarian cancer (OC) remains one of the most lethal gynecological malignancies, mainly because it is frequently diagnosed at advanced stages due to nonspecific symptoms and the lack of effective screening strategies. Long non-coding RNAs (lncRNAs) have emerged as key regulators of gene expression, and accumulating evidence implicates them in OC initiation, progression, and treatment response. This review aims to comprehensively summarize the molecular mechanisms of lncRNAs in OC, examine their clinical potential as biomarkers, and discuss emerging technologies that are about to advance lncRNA research and therapeutics in OC. Methods: A comprehensive review of published studies investigating lncRNA expression, function, and clinical relevance in OC was conducted. Mechanistic insights were integrated across multiple regulatory levels, including epigenetic, transcriptional, post-transcriptional, and post-translational control. Advances in transcriptomic technologies and RNA-targeting techniques were also examined. Results: LncRNAs influence OC through diverse mechanisms, including chromatin remodeling, transcriptional regulation, RNA splicing, mRNA stability, protein modulation, competing endogenous RNA networks, and nuclear organization. Their dysregulation is linked to tumor progression, metastasis, chemoresistance, and poor patient outcomes. Numerous lncRNAs exhibit diagnostic and prognostic value, underscoring their clinical potential. Advances in long-read sequencing have improved lncRNA annotation and isoform resolution, while CRISPR-Cas13 offers a potential approach for selective RNA-targeted therapy. Conclusions: LncRNAs are critical molecules in OC development and progression, holding potential in advancing OC diagnosis, prognosis, and treatment. Continued integration of functional studies, advanced sequencing technologies, and RNA-targeting approaches can facilitate the clinical translation of lncRNAs for early OC diagnosis and management. Full article

Five rare variants in BRIP1/FANCJ, initially identified in ovarian cancer (OC) or breast cancer (BC) cases by the adult hereditary cancer clinics, were investigated for their candidacy as clinically relevant variants. These variants were investigated genetically in a population exhibiting genetic drift and molecularly assayed for biological impact. Using in silico tools, population-based genetic databases and other resources, three of the five reported BRIP1 variants were likely to be damaging: c.797C>T; p.Thr266Met, c.2087C>T; p.Pro696Leu and c.2990_2993delCAAA; p.Thr997ArgfsTer61. The carrier frequencies ranged from 0 to 0.7% in ancestry-defined cancer groups comprising 47 OC families, 49 hereditary breast and ovarian cancer syndrome families, 142 hereditary breast cancer syndrome families, 435 sporadic OC cases and 563 sporadic BC cases and 0–0.2% in 1025 population-matched controls. Multiple carriers of the these variants were identified in additional population-matched cancer cases. Of the five reported BRIP1 variants, p.Thr266Met, p.Pro696Leu and c.2990_2993delCAAA; p.Thr997ArgfsTer61, which were predicted to be damaging, conferred cellular sensitivity to mitomycin C and cisplatin unlike p.Ser139Ala and p.Ala406Ser. Collectively, our investigation implicates BRIP1 c.797C>T; p.Thr266Met, c.2087C>T; p.Pro696Leu and c.2990_2993delCAAA; p.Thr997ArgfsTer61 as deleterious variants in OC and BC. Full article

Ovarian cancer (OC) remains the leading cause of death among gynecologic cancers. Most women diagnosed with OC at advanced stages eventually develop relapse and chemoresistance, leading to poor clinical outcomes. While piRNAs have emerged as critical regulators of gene expression and tumor biology, their specific roles in OC remain to be fully elucidated. This study integrated clinical and computational analyses to investigate the expression pattern and functional relevance of P-element-induced wimpy testis (PIWI)-interacting RNA-823 (piR-823) and its associated protein piwi-like RNA-mediated gene silencing 1 (PIWIL1)/DNA methyltransferase 3B (DNMT3B)/E-cadherin (CDH1) axis in OC tissues from 40 patients, with 20 non-cancer control samples. Expression profiling was performed using qPCR on OC and normal ovarian tissues, followed by correlation and regression analyses. Public databases, including GEPIA, TNM plot, and MethBank, were explored to validate gene expression, methylation status, and pathway enrichment. Our results revealed that piR-823, PIWIL1, and DNMT3B were significantly upregulated in OC tissues (p < 0.001, p = 0.009, and p < 0.001, respectively), and they correlated positively with each other and inversely with CDH1 expression. CDH2, OCT4, and NANOG were significantly upregulated (p = 0.011, p = 0.03, and p < 0.001, respectively), whereas CDH1 expression was significantly downregulated (p < 0.001) in OC tissues. In silico analyses supported DNMT3B-mediated CDH1 promoter methylation, epithelial–mesenchymal transition (EMT), and stemness pathway enrichment. Our integrated computational and clinical analyses indicate that the piR-823/PIWIL1/DNMT3B/CDH1 axis is a putative epigenetic regulator of EMT and cancer stemness in ovarian cancer. Additionally, piR-823 may serve as a promising prognostic biomarker and therapeutic target, offering novel insights into OC pathogenesis and treatment. Full article

Ovarian cancer (OC), the third most common gynecologic malignancy, is characterized by high mortality largely driven by chemotherapy resistance, leading to recurrence and metastasis. Using transcriptomic data from GSE73935, we constructed a weighted gene co-expression network and identified eight hub genes (IGF1R, CDH2, PDGFRA, CDKN1A, SHC1, SPP1, CAV1 and FGF18) associated with cisplatin resistance, among which CDH2 emerged as the most clinically relevant candidate. CDH2 demonstrated moderate diagnostic potential (AUC = 0.792) and was markedly upregulated in cisplatin-resistant A2780/CP70 cells. Independent validation using clinical single-cell RNA-seq data (GSE211956) confirmed its selective enrichment in resistant tumor cell subpopulations. Gene set enrichment analysis linked elevated CDH2 expression to p53 signaling, DNA replication, nucleotide excision repair, and Toll-like receptor pathways, with qPCR supporting upregulation of key downstream genes in resistant cells. Immune deconvolution further indicated that high CDH2 expression correlated with increased infiltration of NK cells, Tregs, macrophages, and neutrophils, and immunohistochemistry verified CDH2 overexpression in cisplatin-resistant tissues. In addition, virtual screening and drug sensitivity profiling identified several FDA-approved agents with potential relevance to CDH2-associated drug response. These findings indicate that CDH2 may serve as a candidate marker associated with cisplatin response in OC, and its association with immune cell infiltration provides further insight into mechanisms potentially underlying chemoresistance. Full article

Background/Objectives: Peritoneal carcinomatosis is the leading cause of death in advanced ovarian cancer (AOC). Mesothelial cells lining the peritoneum modulate tumor implantation, yet the role of their apoptosis in metastasis development remains unclear. This study investigated the relationship between mesothelial cell apoptosis and metastatic spread in ovarian cancer (OC). Methods: The study included 26 patients with AOC, 11 with early-stage OC (EOC), and 13 healthy controls. Apoptotic activity in parietal peritoneal wall and omental mesothelial cells was assessed using the TUNEL technique. Metastases were classified as pushing or infiltrating. Associations with the peritoneal cancer index (PCI), BRCA mutation, and homologous recombination deficiency (HRD) status were analyzed. Results: Mesothelial cells adjacent to AOC metastases exhibited significantly higher apoptotic activity compared to controls (p < 0.05). Apoptosis was greater near infiltrating metastases than near pushing ones in both parietal (p < 0.01) and omental (p = 0.04) sites. The infiltration pattern was consistent between omental and parietal metastases (R = 0.588, p < 0.01). No significant differences in apoptosis were found between EOC and healthy controls, or in tumor and stromal cells between invasion types. Mesothelial apoptosis was independent of PCI, BRCA mutation, and HRD status. Conclusions: Our study suggests that mesothelial cell apoptosis may be associated with peritoneal spread in OC. Mesothelial cell apoptosis is more pronounced near infiltrative-type lesions, independent of BRCA/HRD status. These findings highlight mesothelial apoptosis as a relevant process in peritoneal dissemination. Further studies are needed to clarify its role in ovarian cancer progression. Full article

Ovarian cancer (OC) remains one of the most lethal gynecologic malignancies due to late diagnosis, rapid progression, and frequent chemoresistance. Despite advances in targeted therapy, durable responses are uncommon, underscoring the need for novel multitarget agents capable of modulating key oncogenic networks. Medicarpin, a natural pterocarpan phytoalexin, exhibits diverse pharmacological activities; however, its molecular mechanisms in OC are poorly defined. This study employed an integrative in silico framework combining network pharmacology, pathway enrichment, molecular docking, and survival analysis to elucidate medicarpin’s therapeutic landscape in OC. A total of 107 overlapping targets were identified, resulting in a dense protein–protein interaction network enriched in kinase-mediated and apoptotic signaling pathways. Ten hub genes were emphasized: CASP3, ESR1, mTOR, PIK3CA, CCND1, GSK3B, CDK4, PARP1, CHEK1, and ABL1. Gene Ontology and KEGG analyses demonstrated substantial enrichment in the PI3K–Akt/mTOR and prolactin signaling pathways. Docking revealed the stable binding of medicarpin to CASP3 (−6.13 kcal/mol) and ESR1 (−7.68 kcal/mol), supporting its dual regulation of hormonal and apoptotic processes. Although CASP3 and ESR1 expression alone lacked prognostic significance, their network interplay suggests synergistic relevance. Medicarpin exhibits multitarget anticancer potential in OC by modulating kinase-driven and hormone-dependent pathways, warranting further experimental validation. Full article

Background: Ovarian cancer (OC) remains one of the most lethal gynecologic malignancies due to its often-late diagnosis and complex molecular heterogeneity. Understanding the metabolic alterations in OC can provide insights into its pathophysiology and potential therapeutic targets. This study aimed to explore serum metabolomic profiles and their correlation with clinical and pathological features in OC patients. Materials and Methods: Thirty serum samples were collected from patients diagnosed with ovarian tumors (OTs) (n = 24 malignant, n = 6 benign) and undergoing treatment at Careggi University Hospital. Additionally, 47 samples were obtained from age-matched healthy female donors. Serum samples underwent processing and analysis using an H-NMR (Nuclear Magnetic Resonance) platform to identify a panel of metabolites. Correlation analysis between the metabolomic data and clinical parameters was performed using R software (v.4.4.0). Results: Differential metabolomic profiling showed a significant upregulation of metabolites associated with the purine salvage pathway (i.e., hypoxanthine and inosine) and the ketone bodies axis (i.e., acetone, 3-hydroxybutyrate, and acetate) in samples from ovarian tumor (OT) patients compared to healthy donors. Within malignant OC samples, metabolomic profiles significantly correlated with BRCA1/2 mutation status (BRCA1/2-mutated vs. wild-type) and homologous recombination deficiency (HRD) status. Conclusions: The analysis revealed significant variation in specific metabolites such as betaine, creatinine, carnitine, glycerol, and mannose; notably, a downregulation of these metabolites was observed in HRD-positive patients. The study identifies significant metabolomic alterations in OC, implicating pathways such as purine salvage and ketone bodies. Intriguingly, consistent variation in specific metabolites across BRCA/HRD phenotypes underscores their potential as OC biomarkers. Further research is needed to validate these findings and explore their prognostic and therapeutic implications. Full article

The ovary, as the primary organ responsible for reproduction and new life, plays a central role in female development, maturation, and health. Neoplasms arising from the ovary and its associated tissues exhibit substantial heterogeneity in their histopathological and molecular profiles, many of which remain poorly understood. This review aims to summarize recent advances in the understanding of genetic alterations underlying ovarian neoplasms and to explore therapeutic strategies informed by molecular biomarkers and tumor microenvironmental factors. A comprehensive literature search was performed, focusing on genomic alterations, biomarker-guided therapies, and tumor microenvironmental modulation in ovarian cancers. Emphasis was placed on studies addressing lipid mediator pathways and their roles in immune regulation and therapeutic response. Based on diagnostic classifications, recurrent alterations in TP53, MYC, PIK3CA, and KRAS are consistently observed across epithelial and germ cell ovarian tumors, whereas non-epithelial subtypes such as sex cord–stromal tumors (SCSTs) and small-cell carcinoma of the ovary, hypercalcemic type (SCCOHT), are predominantly associated with ARID1A and SMARCA4 mutations, respectively. These findings highlight distinct pathogenic mechanisms linked to specific genetic alterations and reveal potential therapeutic vulnerabilities. Moreover, lipid metabolism has been closely implicated in immune surveillance through STING signaling cascades within innate immune cells, suggesting that lipid mediators and their associated genes may represent promising therapeutic targets in ovarian cancers (OCs). Targeting lipid mediators could be particularly effective in relapsed OCs, as modulating innate immune cells within the tumor microenvironment (TME) may enhance immune surveillance and improve antitumor responses. Integrating genetic and microenvironmental insights offers a promising direction for developing more effective and personalized therapeutic strategies in OC. Full article

Ovarian cancer (OC) represents the most lethal gynecologic malignancy because the majority of patients with OC are diagnosed at advanced stages with peritoneal colonization of OC cells owing to subtle and nonspecific nature of symptoms. Thus, peritoneal colonization-directed therapeutic approaches are urgently needed for patients with advanced OC. Here, we investigated whether Ring-finger protein 126 (RNF126), an E3 ubiquitin ligase that is aberrantly upregulated in epithelial OC tissues, contributes to the peritoneal colonization of OC. RNF126-depleted OC cells showed comparable proliferation under normal culture conditions but displayed decreased growth under floating (anchorage-independent) conditions in vitro. Further analyses showed that RNF126 promoted anoikis resistance in vitro and increased peritoneal colonization in immunodeficient mice in a RING domain-dependent manner. Mechanistically, RNF126 activated the transcriptional factor NF-κB in OC cells under floating conditions in a RING domain-dependent manner, and this NF-κB activation was essential for anchorage-independent growth and peritoneal colonization of OC cells. Thus, RNF126 is a possible target for the prevention and/or therapy of peritoneally colonized OC. Full article

Background: Ovarian cancer remains one of the leading causes of cancer-related mortality among women and constitutes a major unmet medical need. A common treatment-limiting factor for ovarian cancer patients is resistance to Poly(ADP-ribose) polymerase (PARP) inhibitors such as olaparib. Resistance mechanisms include restoration of functional homologous recombination repair, replication fork protection, PARP1 mutations, and increased drug efflux or metabolism. Understanding these cellular and molecular mechanisms is essential for developing more effective therapeutic strategies and improving patient outcomes. Methods: In this study, patient-derived ovarian cancer cells (OC12) in which resistance to olaparib was induced by exposing the cells to increasing concentrations of the drug over multiple treatment cycles were investigated. To compare intracellular olaparib levels in sensitive and resistant cell lines, a UPLC-MS/MS method to quantify olaparib in the range of 1–300 ng/mL was developed. Results: The method was validated for selectivity, calibration curve performance, carryover, dilution integrity, precision, accuracy, matrix effect, and recovery in accordance with ICH M10 guidelines for bioanalytical method validation. Our findings revealed no significant difference in olaparib levels between resistant and sensitive OC12 cells, excluding the involvement of efflux transporters or enhanced metabolism of olaparib in the resistant OC12 ovarian cancer cells. Conclusions: These results shift the future focus toward pharmacodynamic factors as key drivers of olaparib resistance in OC12 cells. Taken together, the developed UPLC-MS/MS analytical method can be successfully applied to quantify intracellular olaparib levels and investigate the potential contribution of drug efflux mechanisms or increased metabolic activity in cells resistant to olaparib treatment. Full article

The complex relationship between human cytomegalovirus (HCMV) and cancer has been of interest since the 1960s. As a highly prevalent human β-herpesvirus, HCMV establishes lifelong latency in CD34+ myeloid progenitor cells and has been implicated as an oncomodulatory virus in various cancers, including glioblastoma multiforme, breast, prostate, colorectal, and ovarian cancer (OC). Recently, discussions have emerged regarding the classification of HCMV as an eighth oncovirus due to the persistence of its nucleic acids and proteins in many tumour types. As one of the deadliest gynaecological cancers, OC is often characterised as the ‘silent killer’ with less than half of women surviving for 5 years, a rate that drops below 20% when detected at advanced stages. Reported effects of HCMV vary between cancers, likely due to differences in tumour type, viral strain, and disease stage. While HCMV infection has been linked to poor OC patient outcomes, its impact on the OC tumour microenvironment (TME) and immune system remains less understood. Investigating HCMV’s potential oncogenic role could provide critical insights into OC progression. This review discusses recent developments on HCMV’s multifaceted roles in OC, including strain heterogeneity, immunomodulation of the TME, dysregulation of inflammatory signalling pathways, and potential therapeutic approaches targeting HCMV in anti-cancer immunotherapies. Full article

Background/Objectives: The treatment of ovarian cancer (OC), which is predominantly diagnosed in advanced stages, poses a significant challenge to modern gynecologic oncology practice. A significant proportion of patients exhibit chemoresistance, underscoring the need for novel therapeutic interventions. This challenge is further compounded by the immunogenic nature of this neoplasm, prompting the exploration of alternative therapies. A notable example is the use of trastuzumab-deruxtecan (T-DXd), an antibody-drug conjugate (ADC), that has demonstrated encouraging outcomes in preliminary studies and has the potential to become a new treatment option. This systematic review aims to prove that. Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) structure was employed to systematically search the PubMed and Scopus databases from December 2024. Furthermore, authors employed materials from the FDA’s official website and registry of clinical trials that are currently recruiting participants for T-DXd’s studies. Eligible studies included randomized controlled trials and observational studies assessing T-DXd in patients with OC. Outcomes of interest were objective response rate (ORR), median overall survival, adverse effects, and progression-free survival. Data was synthesized narratively. Results: Following a thorough review of available literature, 30 scientific papers were selected for inclusion. A total of 598 patients participated in clinical trials. The most common adverse effects were blurred vision and nausea, generally manageable. The risk of bias was low in most studies. Conclusions: T-DXd shows promising efficacy. A comparison of T-DXd with the ADC currently approved for OC therapy reveals that both demonstrate similar median overall survival and ORRs. However, the drug has exhibited significant adverse effects in breast cancer trials and has been studied on a relatively small number of patients. Therefore, further clinical trials focusing on OC patients are necessary to better assess the safety and efficacy of T-DXd in this population. Full article

Cancer remains a global health challenge (18.1 million new cases in 2020), with incidence projected to reach 28 million within two decades. Ovarian cancer (OC) is the deadliest gynecologic malignancy, usually diagnosed at advanced stages and with poorly understood etiology. Emerging evidence implicates reproductive tract and gut microbiota in OC biology. Microbiota shape carcinogenesis via turnover, immunity, and metabolism; dysbiosis promotes DNA damage, inflammation, and carcinogenic metabolites, engaging multiple hallmarks of cancer. In OC, microbes may reach tumors by local ascent, translocation, or hematogenous spread, originating from vagina, upper reproductive tract, peritoneal fluid, or gut. Lactobacillus-dominant vaginal communities support mucosal integrity, whereas anaerobes disrupt barriers, increase inflammation, and correlate with OC risk; mouse models show vaginal dysbiosis accelerates tumor progression. Distinct microbial profiles in upper reproductive sites and peritoneal fluid associated with immune remodeling. Gut dysbiosis drives barrier loss, immune imbalance, and estrogen reactivation. Microbial metabolites (lipopolysaccharides, short-chain fatty acids) modulate oncogenic pathways, altering epithelial–mesenchymal transition, immune evasion, and drug resistance. Across cohorts, OC tissues and fluids show Pseudomonadota/Bacteroidota enrichment and Akkermansia depletion; fecal microbiota from OC patients accelerates tumor growth in mice, whereas Akkermansia supplementation restores antitumor immunity. Antibiotic exposure and platinum resistance associate with reduced diversity and expansion of lactate-producing taxa. Microbiome-informed interventions–diet, probiotics/postbiotics, fecal microbiota transfer, and selective antibiotics–may augment chemotherapy and immunotherapy. Overall, the microbiome is a modifiable determinant of OC risk, progression, and treatment response, warranting rigorous, standardized, multi-omics studies. Full article

Objective: The relationship between surgical outcomes and metastatic sites in ovarian cancer (OC) is known, but the role of metastatic site-specific tumor burden remains unclear. Methods: We prospectively analyzed data from 202 OC patients. We developed a preoperative protocol evaluating tumor burden in 30 metastatic sites and created a predictive score for suboptimal cytoreduction, which was externally validated. Results: MRI-assessed tumor burdens demonstrated superior consistency with surgical findings compared to CT (κ = 0.4–1.0). Three site-specific tumor burdens (diaphragmatic spleen surface, hepatorenal recess, mesentery), upper abdominal tumor burden, and two clinical factors were identified as predictors of suboptimal cytoreduction. The predictive score incorporating these factors achieved an AUC of 0.873 (0.815 externally validated), outperforming metastatic site-integrated scores including the simulated Fagotti score (AUC: 0.656) and Suidan score (AUC: 0.8308). R0 resection rates were inversely correlated with predictive scores: 94.87% for scores of 0–3 versus 8.57% for scores >14. The peak of Youden’s index reached 11, and patients with predictive scores <11 had longer median progression-free survival. Conclusions: We demonstrated that site-specific tumor burden is correlated with surgical outcomes in OC. Incorporating tumor burden into preoperative assessment enhances prediction performance. We developed a clinically applicable tool, marking a shift from evaluating metastatic sites to assessing metastatic site-specific tumor burden. Full article