Outcome In Ovarian Cancer Patients Research Articles

Development and validation of a nomogram for predicting outcomes in ovarian cancer patients with liver metastases

PurposeTo develop and validate a nomogram for predicting the overall survival (OS) of ovarian cancer patients with liver metastases (OCLM).MethodsThis study identified 821 patients in the Surveillance, Epidemiology, and End Results (SEER) database. All patients were randomly divided in a ratio of 7:3 into a training cohort (n = 574) and a validation cohort (n = 247). Clinical factors associated with OS were assessed using univariate and multivariate Cox regression analyses, and backward stepwise regression was applied using the Akaike information criterion (AIC) to select the optimal predictor variables. The nomogram for predicting the OS of the OCLM patients was constructed based on the identified prognostic factors. Their prediction ability was evaluated using the concordance index (C-index), receiver operating characteristic (ROC) curve, calibration curve, and decision curves analysis (DCA) in both the training and validation cohorts.ResultsWe identified factors that predict OS for OCLM patients and constructed a nomogram based on the data. The ROC, C-index, and calibration analyses indicated that the nomogram performed well over the 1, 2, and 3-year OS in both the training and validation cohorts. Additionally, in contrast to the External model from multiple perspectives, our model shows higher stability and accuracy in predictive power. DCA curves, NRI, and IDI index demonstrated that the nomogram was clinically valuable and superior to the External model.ConclusionWe established and validated a nomogram to predict 1,2- and 3-year OS of OCLM patients, and our results may also be helpful in clinical decision-making.

Impact of metabolism-related markers on outcomes in ovarian cancer patients: Findings of the MITO16A/MaNGO-OV2 trial.

In ovarian cancer, expression of metabolism-related markers has been investigated in several studies focusing on individual markers; however, a parallel quantitative evaluation of markers mapping to distinct metabolic processes and their prognostic value in large patient cohorts is still lacking. Here, by using immunohistochemistry followed by digital pathology, we investigated the expression of several markers related to glycolysis including monocarboxylate transporter 1 and 4 (MCT1, MCT4), glutamine metabolism (glutaminase, GLS) and hypoxia/acidosis (carbonic anhydrase 9, CA IX) in tissue microarrays of > 300 patients recruited in the MITO16A clinical trial, which involved treatment of ovarian cancer patients with carboplatin/taxol plus bevacizumab. Regarding the prognostic impact of these markers, results indicate that GLS expression correlated with progression-free survival, but this effect disappeared when data were corrected for multiple testing. All other markers showed no correlation with clinical outcome. These results indicate marked heterogeneity of expression of metabolism-associated markers in ovarian cancer; however, there was a lack of association with clinical benefit after chemotherapy/anti-vascular endothelial growth factor treatment. Notwithstanding the lack of prognostic value, knowledge of the pattern of expression of these biomarkers in tumors can be useful for patient stratification purposes when new drugs targeting these metabolic pathways will be tested.

Investigating PPT2’s role in ovarian cancer prognosis and immunotherapy outcomes

Ovarian cancer (OC) remains the primary cause of mortality among gynecological malignancies, and the identification of reliable molecular biomarkers to prognosticate OC outcomes is yet to be achieved. The gene palmitoyl protein thioesterase 2 (PPT2), which has been sparsely studied in OC, was closely associated with metabolism. This study aimed to determine the association between PPT2 expression, prognosis, immune infiltration, and potential molecular mechanisms in OC. We obtained the RNA-seq and clinical data from The Cancer Genome Atlas (TCGA), The Genotype-Tissue Expression (GTEx) and Gene Expression Omnibus (GEO) databases, then Kaplan-Meier analysis, univariate Cox regression, multivariate Cox regression, nomogram, and calibration were conducted to assess and verify the role of PPT2. Gene set enrichment analysis (GSEA) was used to figure out the closely correlated pathways with PPT2. Overexpression experiment was performed to explore the function of PPT2. Our findings showed that PPT2 mRNA expression was apparent down-regulation in OC tissue compared to normal ovarian tissues in TCGA, GTEx datasets, and GEO datasets. This differential expression was also confirmed in our in-house datasets at both the mRNA and protein levels. Decreased PPT2 expression correlated with lower survival rates in TCGA, several GEO datasets, and our in-house datasets. Multivariate analysis revealed that PPT2 was an independent factor in predicting better outcomes for OC patients in TCGA and GEO. A negative correlation was revealed between immune infiltration and PPT2 expression through Single-sample GSEA (ssGSEA). Additionally, PPT2 was negatively correlated with an up-regulated immune score, stromal score, and estimate score, suggesting that patients with low PPT2 expression might benefit more from immunotherapy. Numerous chemical agents showed lower IC50 in patients with high PPT2 expression. In single-cell RNA sequencing (scRNA-seq) analysis of several OC datasets, we found PPT2 was mainly expressed in endothelial cells. Furthermore, we found that PPT2 inhibited OC cell proliferation in vitro. Our results demonstrated that PPT2 was considered a favorable prognostic biomarker for OC and may be vital in predicting response to immunotherapy and chemotherapy. Further research was needed to fully understand the relationship between PPT2 and immunotherapy efficacy in OC patients.

Knowledge mapping and visualization of trends in immunotherapy for ovarian cancer over the past five years: a bibliometric analysis.

This study conducts a bibliometric literature analysis to explore trends in immunotherapy for ovarian cancer from 2019 to 2023. An extensive online literature search was conducted in the Web of Science Core Collection database to identify English-language articles and reviews related to "trends in immunotherapy", and "ovarian cancer". statistical analysis was performed using VOSviewer to visualize and compare nations, institutions, and journals simultaneously. Our findings highlight contributions by 118 nations, led by the People's Republic of China with 3,167 contributions; Germany followed with 558 and Italy having 547. Of all publications made between 2019-2023, "Frontiers Immunology" had the most publications with 546 total records followed by "cancers ", and "frontiers in oncology" being the most heavily relied upon categories. Annually publication trends increased until 2022 but then declined considerably as a peak of highly-cited papers occurring between 2019 and 2022. Our bibliometric analysis not only maps the evolution of immunotherapy research in ovarian cancer but also provides actionable insights for advancing scientific progress. By identifying emerging trends and key areas, future research can strategically enhance treatment strategies and outcomes for ovarian cancer patients.

SLC45A4 is involved in malignant progression of ovarian cancer through glycolytic metabolic reprogramming

Tumor cells promote malignant behaviors such as proliferation, invasion, and metastasis of cancer cells through glucose metabolic reprogramming, but the role of the H-dependent sugar cotransporter SLC45A4 in regulating metabolic reprogramming in ovarian cancer (OC) remains largely unknown. This study aimed to investigate the effects of SLC45A4 silencing on the transcriptome spectrum of ovarian cancer cells (OCC), glucose uptake, lactic acid production, intracellular ATP levels, and the expression and activity of HIF-α glycolysis signaling pathway. The results showed that SLC45A4 is overexpressed in OC and its elevated expression correlates with adverse clinical outcomes in OC patients. Silencing of SLC45A4 significantly inhibited the proliferation, invasion, and metastasis of OCC by suppressing glucose uptake and glycolysis, and it also reduced the expression of HIF-α glycolysis signaling pathway in OC tissues. In vivo experiments using shRNA to knock down SLC45A4 in xenograft models in nude mice demonstrated a significant inhibition of tumor growth. These findings suggest that SLC45A4 silencing can restrain the malignant progression of OC by inhibiting glucose uptake in OCC and affecting the reprogramming of glycolytic energy metabolism, indicating that SLC45A4 may serve as a potential therapeutic target for OC intervention.

A herbal pair of Scutellaria barbata D. Don and Scleromitrion diffusum (Willd.) R.J. Wang induced ferroptosis in ovarian cancer A2780 cells via inducing heme catabolism and ferritinophagy

ObjectiveDespite the combination of Scutellaria barbata D. Don and Scleromitrion diffusum (Willd.) R.J. Wang (SB-SD) being a recognized Chinese medicinal herbal pair that is commonly used in the treatment of ovarian cancer, there is a poor understanding of their pharmacological mechanisms. This study examines the antitumor properties and potential mechanisms of SB-SD on human ovarian cancer A2780 cells through a multi-omics approach, establishing a pharmacological basis for clinical utilization. MethodsA range of mass ratios and reagents were used in the hot reflux extraction of SB-SD. The inhibitory effect of the SB-SD extracts on A2780 cell proliferation was assessed using the cell-counting kit 8 assay. A zebrafish tumor implantation model was used to evaluate the effects of SB-SD extracts on tumor growth and metastasis in vivo. Transcriptomics and proteomics were used to investigate alterations in biological pathways in A2780 cells after treatment with different concentrations of SB-SD extract. Cell cycle, cell apoptosis, intracellular free iron concentration, intracellular reactive oxygen species (ROS) concentration, malondialdehyde (MDA), and mitochondrial membrane potential were measured. Real-time quantitative reverse transcription polymerase chain reaction and Western blotting were utilized to investigate the effects of heme catabolism and ferritinophagy on ferroptosis induced by SB-SD extract in A2780 cells. ResultsThe 70% ethanol extract of SB-SD (a mass ratio of 4:1) inhibited A2780 cell proliferation significantly with a half maximal inhibitory concentration of 660 μg/mL in a concentration- and time-dependent manner. Moreover, it effectively suppressed tumor growth and metastasis in a zebrafish tumor implantation model. SB-SD extract induced the accumulation of free iron, ROS, MDA, and mitochondrial damage in A2780 cells. The mechanisms might involve the upregulated expression of ferritinophagy-related genes microtubule-associated protein 1 light chain 3, autophagy-related gene 5, and nuclear receptor coactivator 4. ConclusionSB-SD extract effectively inhibited the development of ovarian cancer both in vitro and in vivo. Its mechanism of action involved inducing ferroptosis by facilitating heme catabolism and ferritinophagy. This herbal pair holds promise as a potential therapeutic option for ovarian cancer treatment and may be utilized in combination with routine treatment to improve the treatment outcomes of ovarian cancer patients.Please cite this article as: Wang Z, Liu M, Li GX, Zhang L, Ding KY, Li SQ, Gao BQ, Chen P, Choe HC, Xia LY, Yang YT, Liu Y, Sui X, Ma JN, Zhang L. A herbal pair of Scutellaria barbata D. Don and Scleromitrion diffusum (Willd.) R.J. Wang induced ferroptosis in ovarian cancer A2780 cells via inducing heme catabolism and ferritinophagy. J Integr Med. 2024; Epub ahead of print.

S100A1 overexpression stimulates cell proliferation and is predictive of poor outcome in ovarian cancer.

Members of the S100 gene family are frequently dysregulated in various cancers, including ovarian cancer (OC). Despite this, the prognostic implications of individual S100 genes in OC remain poorly understood. This study aimed to explore the prognostic significance of S100A1 expression in OC and assess its potential as a therapeutic target. To investigate the role of S100A1 in OC, we utilized the Gene Expression Profiling Interactive Analysis (GEPIA) database and the University of ALabama at Birmingham Cancer Data Analysis Portal (UALCAN) database. Protein levels of S100A1 in OC tissues were assessed using western blotting and immunohistochemistry. Bioinformatics analyses were performed to correlate S100A1 expression with clinical outcomes. Functional assays were conducted to evaluate the impact of S100A1 knockout on OC cell proliferation and migration. Additionally, we investigated the effect of S100A1 on ferroptosis and lipid reactive oxygen species (ROS) levels in tumor cells. Our analyses revealed that S100A1 protein levels were significantly elevated in OC tissues compared to normal tissues. Elevated S100A1 expression was associated with poor clinical outcomes in OC patients. Functional assays demonstrated that the knockout of S100A1 led to a decrease in both proliferation and migration of OC cells in vitro. Furthermore, S100A1 was found to inhibit ferroptosis in OC cells, resulting in lower levels of lipid ROS within tumor cells. High levels of S100A1 are indicative of adverse clinical outcomes in OC. Our findings suggest that S100A1 could serve as a valuable prognostic marker and a potential therapeutic target for OC treatment.

199P Association of homologous recombination deficiency status with outcomes for ovarian cancer patients treated with olaparib, and exploration of other biomarkers of relapse and survival

199P Association of homologous recombination deficiency status with outcomes for ovarian cancer patients treated with olaparib, and exploration of other biomarkers of relapse and survival

1196P Organoid growth-based oncological sensitivity test (OncoSensi) for predicting adjuvant therapy outcomes in ovarian cancer patients

1196P Organoid growth-based oncological sensitivity test (OncoSensi) for predicting adjuvant therapy outcomes in ovarian cancer patients

Drp1 splice variants regulate ovarian cancer mitochondrial dynamics and tumor progression

Aberrant mitochondrial fission/fusion dynamics are frequently associated with pathologies, including cancer. We show that alternative splice variants of the fission protein Drp1 (DNM1L) contribute to the complexity of mitochondrial fission/fusion regulation in tumor cells. High tumor expression of the Drp1 alternative splice variant lacking exon 16 relative to other transcripts is associated with poor outcome in ovarian cancer patients. Lack of exon 16 results in Drp1 localization to microtubules and decreased association with mitochondrial fission sites, culminating in fused mitochondrial networks, enhanced respiration, changes in metabolism, and enhanced pro-tumorigenic phenotypes in vitro and in vivo. These effects are inhibited by siRNAs designed to specifically target the endogenously expressed transcript lacking exon 16. Moreover, lack of exon 16 abrogates mitochondrial fission in response to pro-apoptotic stimuli and leads to decreased sensitivity to chemotherapeutics. These data emphasize the pathophysiological importance of Drp1 alternative splicing, highlight the divergent functions and consequences of changing the relative expression of Drp1 splice variants in tumor cells, and strongly warrant consideration of alternative splicing in future studies focused on Drp1.

Comprehensive analysis of hub genes associated with cisplatin-resistance in ovarian cancer and screening of therapeutic drugs through bioinformatics and experimental validation

BackgroundTo identify key genes associated with cisplatin resistance in ovarian cancer, a comprehensive analysis was conducted on three datasets from the GEO database and through experimental validation.MethodsGene expression profiles were retrieved from the GEO database. DEGs were identified by comparing gene expression profiles between cisplatin-sensitive and resistant ovarian cancer cell lines. The identified genes were further subjected to GO, KEGG, and PPI network analysis. Potential inhibitors of key genes were identified through methods such as LibDock nuclear molecular docking. In vitro assays and RT-qPCR were performed to assess the expression levels of key genes in ovarian cancer cell lines. The sensitivity of cells to chemotherapy and proliferation of key gene knockout cells were evaluated through CCK8 and Clonogenic assays.ResultsResults showed that 12 genes influenced the chemosensitivity of the ovarian cancer cell line SKOV3, and 9 genes were associated with the prognosis and survival outcomes of ovarian cancer patients. RT-qPCR results revealed NDRG1, CYBRD1, MT2A, CNIH3, DPYSL3, and CARMIL1 were upregulated, whereas ERBB4, ANK3, B2M, LRRTM4, EYA4, and SLIT2 were downregulated in cisplatin-resistant cell lines. NDRG1, CYBRD1, and DPYSL3 knock-down significantly inhibited the proliferation of cisplatin-resistant cell line SKOV3. Finally, photofrin, a small-molecule compound targeting CYBRD1, was identified.ConclusionThis study reveals changes in the expression level of some genes associated with cisplatin-resistant ovarian cancer. In addition, a new small molecule compound was identified for the treatment of cisplatin-resistant ovarian cancer.

The Influence of Inflammatory and Nutritional Status on the Long-Term Outcomes in Advanced Stage Ovarian Cancer.

Despite improving surgical techniques and achieving more often complete debulking procedures, certain patients with advanced-stage ovarian cancer still have a very poor prognosis. The aim of the current paper is to investigate whether inflammatory and nutritional status can predict the long-term outcomes of ovarian cancer patients. A retrospective analysis of 57 cases diagnosed with advanced-stage ovarian cancer submitted to surgery as first intent therapy was carried out. In all cases, the preoperative status was determined by calculating the CRP/albumin ratio, as well as the Glasgow score, the modified Glasgow score and the prognostic nutritional index. Patients presenting higher values of the CRP/albumin ratio, with a higher Glasgow score, modified Glasgow score and prognostic nutritional index (PNI), were more frequently associated with incomplete debulking surgery, a higher peritoneal carcinomatosis index and poorer overall survival (20 months versus 9 months for the CRP/albumin ratio p = 0.011, 42 versus 27 versus 12 months for the Glasgow score p = 0.042, 50 versus 19 versus 12 months for the modified Glasgow score, p = 0.001, and 54 months versus 21 months, p = 0.011 for the prognostic nutritional index). A strong relationship between the nutritional and inflammatory status in advanced-stage ovarian cancer seems to exist.

Dual-Targeted Zeolitic Imidazolate Frameworks Drug Delivery System Reversing Cisplatin Resistance to Treat Resistant Ovarian Cancer.

Ovarian cancer cells are prone to acquire tolerance to chemotherapeutic agents, which seriously affects clinical outcomes. The development of novel strategies to enhance the targeting of chemotherapeutic agents to overcome drug resistance and minimize side effects is significant for improving the clinical outcomes of ovarian cancer patients. We employed folic acid (FA)-modified ZIF-90 nanomaterials (FA-ZIF-90) to deliver the chemotherapeutic drug, cisplatin (DDP), via dual targeting to improve its targeting to circumvent cisplatin resistance in ovarian cancer cells, especially by targeting mitochondria. FA-ZIF-90/DDP could rapidly release DDP in response to dual stimulation of acidity and ATP in tumor cells. FA-ZIF-90/DDP showed good blood compatibility. It was efficiently taken up by human ovarian cancer cisplatin-resistant cells A2780/DDP and aggregated in the mitochondrial region. FA-ZIF-90/DDP significantly inhibited the mitochondrial activity and metastatic ability of A2780/DDP cells. In addition, it effectively induced apoptosis in A2780/DDP cells and overcame cisplatin resistance. In vivo experiments showed that FA-ZIF-90/DDP increased the accumulation of DDP in tumor tissues and significantly inhibited tumor growth. FA-modified ZIF-90 nanocarriers can improve the tumor targeting and anti-tumor effects of chemotherapeutic drugs, reduce toxic side effects, and are expected to be a novel therapeutic strategy to reverse drug resistance in ovarian cancer.

RWD35 Assessing Pharmacoequity in PARPi Therapy Utilization and Outcomes in Ovarian Cancer Patients: Insights From Real-World Evidence

RWD35 Assessing Pharmacoequity in PARPi Therapy Utilization and Outcomes in Ovarian Cancer Patients: Insights From Real-World Evidence

Effects of niraparib dose reduction on short-term outcomes in ovarian cancer patients

ObjectivesDespite the individualized starting dose for maintenance therapy in ovarian cancer, the niraparib dose reduction rate remains high. The aim of this study was to evaluate the impact of niraparib...

Ovarian carcinosarcoma is highly aggressive compared to other ovarian cancer histotypes

BackgroundOvarian carcinosarcoma (OCS) is an unusual ovarian cancer type characterized by distinct carcinomatous and sarcomatous components. OCS has been excluded from many of the pan-histotype studies of ovarian carcinoma, limiting our understanding of its behavior.MethodsWe performed a multi-cohort cross-sectional study of characteristics and outcomes in ovarian cancer patients from Scotland (n=2082) and the Surveillance, Epidemiology and End Results Program (SEER, n=44946) diagnosed with OCS or one of the other major histotypes: high grade serous (HGSOC), endometrioid (EnOC), clear cell (CCOC), mucinous (MOC) or low grade serous ovarian carcinoma (LGSOC). Differences in overall survival were quantified using Cox regression models to calculate hazard ratios (HR).ResultsAcross both cohorts, OCS patients were significantly older at diagnosis compared to all other histotypes (median age at diagnosis 69 and 67 in Scottish and SEER cohorts) and demonstrated the shortest survival time upon univariable analysis. Within the Scottish cohort, 59.3% and 16.9% of OCS patients presented with FIGO stage III and IV disease, respectively; this was significantly higher than in EnOC, CCOC or MOC (P<0.0001 for all), but lower than in HGSOC (P=0.004). Multivariable analysis accounting for other prognostic factors identified OCS as independently associated with significantly shorter survival time compared to HGSOC, EnOC, LGSOC and MOC in both the Scottish (multivariable HR vs OCS: HGSOC 0.45, EnOC 0.39, LGSOC 0.26, MOC 0.43) and SEER cohorts (multivariable HR vs OCS: HGSOC 0.59, EnOC 0.34, LGSOC 0.30, MOC 0.81). Within the SEER cohort, OCS also demonstrated shorter survival compared to CCOC (multivariable HR 0.63, 95% CI 0.58-0.68), but this was not replicated within the Scottish cohort (multivariable HR for CCOC: 1.05, 95% CI 0.74-1.51). Within early-stage disease specifically (FIGO I-II or SEER localized stage), OCS was associated with the poorest survival of all histotypes across both cohorts. In the context of late-stage disease (FIGO III-IV or SEER distant stage), OCS, MOC and CCOC represented the histotypes with poorest survival.ConclusionOCS is a unique ovarian cancer type that affects older women and is associated with exceptionally poor outcome, even when diagnosed at earlier stage. New therapeutic options are urgently required to improve outcomes.

Low PDE4A expression promoted the progression of ovarian cancer by inducing Snail nuclear translocation

Widespread metastasis is the primary reason for the high mortality associated with ovarian cancer (OC), and effective targeted therapy for tumor aggressiveness is still insufficient in clinical practice. Therefore, it is urgent to find new targets to improve prognosis of patients. PDE4A is a cyclic nucleotide phosphodiesterase that plays a crucial role in the occurrence and development in various malignancies. Our study firstly reported the function of PDE4A in OC. Expression of PDE4A was validated through bioinformatics analysis, RT-qPCR, Western blot, and immunohistochemistry. Additionally, its impact on cell growth and motility was assessed via in vitro and in vivo experiments. PDE4A was downregulated in OC tissues compared with normal tissues and low PDE4A expression was correlated with poor clinical outcomes in OC patients. The knockdown of PDE4A significantly promoted the proliferation, migration and invasion of OC cells while overexpression of PDE4A resulted in the opposite effect. Furthermore, smaller and fewer tumor metastatic foci were observed in mice bearing PDE4A-overexpressing OVCAR3 cells. Mechanistically, downregulation of PDE4A expression can induce epithelial-mesenchymal transition (EMT) and nuclear translocation of Snail, which suggests that PDE4A plays a pivotal role in suppressing OC progression. Notably, Rolipram, the PDE4 inhibitor, mirrored the effects observed with PDE4A deletion. In summary, the downregulation of PDE4A appears to facilitate OC progression by modulating the Snail/EMT pathway, underscoring the potential of PDE4A as a therapeutic target against ovarian cancer metastasis.

ANGPTL3 diminishes the resistance of ovarian cancer to paclitaxel by blocking the PI3K-AKT-mTOR signaling pathway

Angiopoietin-like protein 3 (ANGPTL3) is key in ovarian cancer (OC) cell growth and metastasis, notably by enhancing natural killer cells' capacity for inducing cell toxicity and apoptosis. However, its role in influencing chemotherapy resistance in OC remains ambiguous. In this study, we discovered a correlation between reduced ANGPTL3 levels and a less favorable outcome in OC patients using the Kaplan-Meier Plotter database. Lower levels of ANGPTL3 were detected in paclitaxel (PTX)-resistant OC tissues and cell lines via western blotting and immunohistochemistry. To investigate ANGPTL3's effects, we established SKOV3/PTX and 2780/PTX as PTX-resistant OC cell lines by incrementally increasing PTX exposure and then transfecting them with overexpress ANGPTL3 (OE-ANGPTL3) lentivirus. We conducted various assays such as CCK-8, colony formation, Edu staining, flow cytometry, and transwell to investigate the impact of ANGPTL3 on PTX resistance. Additionally, this effect was examined in a mouse subcutaneous xenograft model. Both in vitro and in vivo experiments demonstrated that ANGPTL3 overexpression mitigated PTX resistance in OC cells by inactivating the PI3K-AKT-mTOR pathway. In summary, our research reveals that ANGPTL3 enhances PTX sensitivity in OC by downregulating the PI3K-AKT-mTOR pathway. The study of this study suggest that ANGPTL3 could serve as a valuable therapeutic target for OC, signifying its clinical relevance in OC management.

Proteomic profiles of peritoneal fluid-derived small extracellular vesicles correlate with patient outcome in ovarian cancer.

Cancer-derived small extracellular vesicles (sEVs) are capable of modifying the tumor microenvironment and promoting tumor progression. Ovarian cancer (OvCa) is a lethal malignancy that preferentially spreads through the abdominal cavity. Thus, the secretion of such vesicles into the peritoneal fluid could be a determinant factor in the dissemination and behavior of this disease. We designed a prospective observational study to assess the impact of peritoneal fluid-derived sEVs (PFD-sEVs) in OvCa clinical outcome. For this purpose, 2 patient cohorts were enrolled: patients with OvCa who underwent a diagnostic or cytoreductive surgery and nononcological patients, who underwent abdominal surgery for benign gynecological conditions and acted as the control group. Systematic extraction of PFD-sEVs from surgical samples enabled us to observe significant quantitative and qualitative differences associated with cancer diagnosis, disease stage, and platinum chemosensitivity. Proteomic profiling of PFD-sEVs led to the identification of molecular pathways and proteins of interest and to the biological validation of S100A4 and STX5. In addition, unsupervised analysis of PFD-sEV proteomic profiles in high-grade serous ovarian carcinomas (HGSOCs) revealed 2 clusters with different outcomes in terms of overall survival. In conclusion, comprehensive characterization of PFD-sEV content provided a prognostic value with potential implications in HGSOC clinical management.

Abstract 2035: A Benzenesulfornamide with potential to improve chemoresponse of ovarian cancer through activation of AMPK and immunogenic cell death

Abstract Introduction: Ovarian cancer is a leading cause of death among women globally often characterized by poor prognosis and aggressive tumor growth. The therapeutic outcomes of ovarian cancer patients are limited by the development of acquired chemoresistance and the lack of targeted therapies. This study aimed to understand the mechanism in which a benzenesulfornamide named Y3 enhances the efficacy of chemotherapeutic agents. Y3 was previously identified by our team as an activator of AMPK with the activity to induce immunogenic cell death of ovarian cancer cells. Material and Methods: Patient-derived ovarian cancer cell lines were pretreated with Y3 for 3 h before treatment of carboplatin or paclitaxel. Celltiter Glo assay was performed to determine the impact of Y3 pretreatment on the IC50 values of carboplatin or paclitaxel after 48 h. Apoptosis was evaluated using Annexin VI/PI staining and Caspase 3 activity assays. The role of AMPK pathway was assessed using AMPK siRNAs and western blot. The potential of Y3 to enhance immunogenic cell death induced by carboplatin or paclitaxel was evaluated in a syngeneic mouse model of ovarian cancer using a vaccination assay. The control group mice were vaccinated by subcutaneously injecting mouse ovarian cancer cells treated by carboplatin in vitro for 24 h into the left flank. The test group mice were vaccinated by injecting Y3-carboplatin co-treated cells. One week after vaccination, untreated live cancer cells were injected into the right flank of both groups. Tumor growth was monitored. Results: Ovarian cancer cell lines pretreated with Y3 showed decreased IC50 values for carboplatin and paclitaxel treatments. The apoptotic cell populations stained by Annexin VI were increased in the Y3 pretreated in comparisons with the single treatment groups. Caspase-3 activity validated the results of Annexin VI/PI staining assay. AMPK knockdown by siRNAs effectively reduced the levels of phospho-AMPK that was induced by Y3, which also dampened the Y3-promoted chemotherapeutic effects on ovarian cancer cells. In the in vivo vaccination assay, tumor growth in the right flank was suppressed in the mice vaccinated with Y3-carboplatin co-treated cells to an extend that is more significant than the control group. Conclusion: Y3 pretreatment increased the sensitivity of ovarian cancer cell lines to carboplatin and paclitaxel. The effects of Y3 on ovarian cancer cells depend on the activation of AMPK. Y3 enhances the immunogenicity of carboplatin-treated ovarian cancer cells. Citation Format: Juhyun Kim, Nia Montero, Shefali Sharma, Miranda Mansolf, Kevin Yang, Tobias Hartwich, Yang Yang-Hartwich. A Benzenesulfornamide with potential to improve chemoresponse of ovarian cancer through activation of AMPK and immunogenic cell death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2035.