Outcome In Ovarian Cancer Patients Research Articles

A novel SIK2 inhibitor SIC-19 exhibits synthetic lethality with PARP inhibitors in ovarian cancer

PurposeOvarian cancer patients with HR proficiency (HRP) have had limited benefits from PARP inhibitor treatment, highlighting the need for improved therapeutic strategies. In this study, we developed a novel SIK2 inhibitor, SIC-19, and investigated its potential to enhance the sensitivity and expand the clinical utility of PARP inhibitors in ovarian cancer. MethodsThe SIK2 protein was modeled using a Molecular Operating Environment (MOE), and the most favorable model was selected based on a GBVI/WSA dG scoring function. The Chembridge Compound Library was screened, and the top 20 candidate compounds were tested for their interaction with SIK2 and downstream substrates, AKT-pS473 and MYLK-pS343. SIC-19 emerged as the most promising drug candidate and was further evaluated using multiple assays. ResultsSIC-19 exhibited selective and potent inhibition of SIK2, leading to its degradation through the ubiquitination pathway. The IC50 of SIC-19 correlated inversely with endogenous SIK2 expression in ovarian cancer cell lines. Treatment with SIC-19 significantly inhibited cancer cell growth and sensitized cells to PARP inhibitors in vitro, as well as in ovarian cancer organoids and xenograft models. Mechanistically, SIK2 knockdown and SIC-19 treatment reduced RAD50 phosphorylation at Ser635, prevented nuclear translocation of RAD50, disrupted nuclear filament assembly, and impaired DNA homologous recombination repair, ultimately inducing apoptosis. These findings highlight the crucial role of SIK2 in the DNA HR repair pathway and demonstrate the significant PARP inhibitor sensitization achieved by SIC-19 in ovarian cancer. ConclusionsSIC-19, a novel SIK2 inhibitor, effectively inhibits tumor cell growth in ovarian cancer by interfering with RAD50-mediated DNA HR repair. Furthermore, SIC-19 enhances the efficacy of PARP inhibitors, providing a promising therapeutic strategy to improve outcomes for ovarian cancer patients.

Machine learning constructs a T cell-related signature for predicting prognosis and drug sensitivity in ovarian cancer.

The leading cause of death related to gynecologic cancer is ovarian cancer, which typically has a poor prognosis. T cells are referred to as key mediators of immunosurveillance and tumor eradication, and unbalanced regulation or lack of T cells in tumors result in immunotherapy resistance. The identification of T cell related markers depended on single-cell RNA-seq analysis. Using data from multiple datasets, including TCGA, GSE14764, GSE26193, GSE26712, and GSE140082, we constructed a prognostic signature called TRS (T cell-related signature) using 10 different machine learning algorithms. The correlation between TRS and drug sensitivity were analyzed using the data from GSE91061 and IMvigor210 dataset. PlsRcox method based TRS was as a risk factor for the clinical outcome of ovarian cancer patients. In comparison with stage, grade and many prognostic signatures, the performance of our TRS in evaluating the clinical outcome was better in ovarian cancer. TRS-based risk score showed distinct association with the level of ESTIMATE score, immune-related function score and immune cells. Moreover, TRS could be used to predict the immunotherapy response and chemotherapy response in ovarian cancer. In conclusion, we constructed a powerful TRS in ovarian cancer, which could accurately predict the clinical outcome of patients and be used to predict the immunotherapy response and chemotherapy response.

Closing the diagnostic gap: Liquid biopsy potential to transform ovarian cancer outcomes in sub-Saharan Africa.

Ovarian cancer presents a significant health challenge in sub-Saharan Africa (SSA), where late-stage diagnosis contributes to high mortality rates. This diagnostic gap arises from limited resources, poor healthcare infrastructure, and a lack of awareness about the disease. However, a potential game-changer is emerging in the form of liquid biopsy (LB), a minimally invasive diagnostic method. This paper analyses the current diagnostic gap in ovarian cancer in SSA, highlighting the socio-economic, cultural, and infrastructural factors that hinder early diagnosis and treatment. It discusses the challenges and potential of LB in the context of SSA, emphasizing its cost-effectiveness and adaptability to resource-limited settings. The transformative potential of LB in SSA is promising, offering a safer, more accessible, and cost-effective approach to ovarian cancer diagnosis. This paper provides recommendations for future directions, emphasizing the need for research, infrastructure development, stakeholder engagement, and international collaboration. By recognizing the transformative potential of LB and addressing the diagnostic gap, we can pave the way for early detection, improved treatment, and better outcomes for ovarian cancer patients in SSA. This paper sheds light on a path toward better healthcare access and equity in the region.

An assessment of survival outcomes among ovarian cancer patients at the National and Referral Hospital in Kenya.

Ovarian cancer has been shown to have poor survival outcomes attributed to late presentation. In Kenya, information on the survival outcomes of ovarian cancer patients is scarce. Therefore, the objective of this study was to examine the survival outcomes among patients with ovarian cancer treated at Kenyatta National Hospital (KNH). A hospital-based retrospective cohort study was performed at KNH to examine the survival outcomes of 112 ovarian cancer patients. The study employed a structured data abstraction tool to acquire patients' relevant socio-demographic and clinical characteristics from the patient's medical records. The data obtained were analyzed using SPSS version 29.0 statistical software. Kaplan-Meier and Cox regression analyses were used to determine the survival outcome and predictors of mortality among ovarian cancer patients, respectively. The mean age of the patients in this study was 51.28 ± 14.24 years. Most patients (59.8%) had evidence of distant metastasis during the follow-up period. One-third (33%) of patients were deceased. The mean-cancer-specific survival time among the study participants was 40.0 ± 3.0 months. The 5-year survival rate was 44%, with most patients experiencing disease progression during the last follow-up. Combination therapy (p < .001) was the only statistically significant predictor of mortality in ovarian cancer patients. The study found that the 5-year survival rate among ovarian cancer patients was poor, with most patients experiencing disease progression during the last follow-up period.

Surgical Treatment and Outcome of Ovarian Cancer Patients With Liver Metastases: Experience of a Tertiary Hepatic and Peritoneal Surface Malignancy Center.

The aim of this study was to describe and evaluate the patterns, perioperative outcomes, and survival rates of patients subjected to hepatic resections for ovarian-derived liver metastasis as part of cytoreductive surgery with or without hyperthermic intraperitoneal chemotherapy (HIPEC). Furthermore, we investigated two subgroups of tumor patterns: hematogenous liver metastasis and infiltrative liver metastatic spread. A retrospective study was conducted. Patients from a University Tertiary Hepatic and Peritoneal Surface Malignancy Center with primary or recurrent ovarian cancer, who underwent liver resection as part of cytoreductive surgery between January 1992 and December 2022, were included. Data from 35 patients were analyzed. Both median overall survival (OS) and disease-specific survival (DSS) were 24.97 months. In a multivariate setting, the combined effect of age, peritoneal carcinomatosis index, body mass index, hematogenous liver metastasis vs. infiltrative spread types, and HIPEC (HR=0.2372; 95%CI=0.0719-0.7823; p=0.0181) over OS was tested. Survival analysis revealed no differences between the two metastatic spread types (OS: p=0.9720; DSS: p=0.9610). Younger age (p=0.0301), splenectomy (p=0.0320), lesser omentectomy (p=0.0178), and right upper quadrant peritonectomy (p=0.0373) were more characteristic for those patients with infiltrative liver metastatic spread. Complete cytoreductive surgery, including hepatic resection is a feasible approach with or without additional HIPEC, which may provide survival benefit for patients with advanced and/or recurrent ovarian cancer. If metastatic and infiltrative liver involvement is suspected, liver-specific imaging is recommended.

PARPis response and outcome of ovarian cancer patients with BRCA1/2 germline mutation and a history of breast cancer.

The aim of this study was to determine the poly (ADP-ribose) polymerase inhibitors (PARPis) response and outcome of ovarian cancer (OC) patients with BRCA1/2 germline mutation and a history of breast cancer (BC). Thirty-nine OC patients with BRCA1/2 germline mutation and a history of BC were included. The clinicopathological characteristics, PARPis response and prognosis were analyzed. The median interval from BC to OC diagnosis was 115.3 months (range=6.4-310.1). A total of 38 patients (38/39, 97.4%) received platinum-based chemotherapy after surgical removal. The majority of these patients were reported to be platinum sensitive (92.1%, 35/38). 21 patients (53.8%) received PARPis treatment with 16 patients (76.2%) for maintenance treatment and 5 patients (5/21, 23.8%) for salvage treatment. The median duration for PARPis maintenance and salvage treatment was 14.9 months (range=2.0-56.9) and 8.2 months (range=5.2-20.7), respectively. In the entire cohort, 5-year progression-free survival (PFS) and overall survival (OS) rate was 33.1% and 78.9%, respectively. Patients with BRCA1 mutation had a non-significantly worse 5-year PFS (28.6% vs. 45.8%, p=0.346) and 5-year OS (76.9% vs. 83.3%, p=0.426) than those with BRCA2 mutation. In patients with stage III-IV (n=31), first line PARPis maintenance treatment associated with a non-significantly better PFS (median PFS: NR vs. 22.4 months; 5-year PFS: 64.3% vs. 21.9%, p=0.096). The current study shows that these patients may have a good response to platinum-based chemotherapy and a favorable survival. And these patients can benefit from PARPis treatment and will likely be suitable candidates for PARPis.

Screening and identification of serum exosomal protein ZNF587B in liquid biopsy for ovarian cancer diagnosis.

Addressing the critical challenge of early ovarian cancer (OC) detection, our study focuses on identifying novel biomarkers by analyzing preoperative peripheral blood exosomes from high-grade serous ovarian cancer (HGSC) patients and healthy controls. Utilizing high-performance liquid chromatography-mass spectrometry-based quantitative proteomics, we isolated and analyzed peripheral blood exosomes to identify differentially expressed proteins (DEPs). This comprehensive analysis, supported by gene ontology enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) database assessments, revealed 28 proteins with decreased abundance and 33 with increased abundance in HGSC patients compared to controls. Notably, Zinc Finger Protein 587B (ZNF587B) exhibited a significant reduction in abundance, confirmed by decreased mRNA and protein levels in HGSC and normal ovarian tissues, consistent with omes exosomal protein expression levels. Immunohistochemical staining further confirmed reduced ZNF587B protein levels in HGSC tissues. The significant correlation between ZNF587B expression levels and tumor stage underscores its potential as a valuable biomarker for early liquid biopsy screening of OC. Our findings suggest ZNF587B plays a crucial role in early HGSC detection, highlighting the importance of further research to validate its clinical utility and improve ovarian cancer patient outcomes.

Enhancing Immunotherapy in Ovarian Cancer: The Emerging Role of Metformin and Statins.

Ovarian cancer metastization is accompanied by the development of malignant ascites, which are associated with poor prognosis. The acellular fraction of this ascitic fluid contains tumor-promoting soluble factors, bioactive lipids, cytokines, and extracellular vesicles, all of which communicate with the tumor cells within this peritoneal fluid. Metabolomic profiling of ovarian cancer ascites has revealed significant differences in the pathways of fatty acids, cholesterol, glucose, and insulin. The proteins involved in these pathways promote tumor growth, resistance to chemotherapy, and immune evasion. Unveiling the key role of this liquid tumor microenvironment is crucial for discovering more efficient treatment options. This review focuses on the cholesterol and insulin pathways in ovarian cancer, identifying statins and metformin as viable treatment options when combined with standard chemotherapy. These findings are supported by clinical trials showing improved overall survival with these combinations. Additionally, statins and metformin are associated with the reversal of T-cell exhaustion, positioning these drugs as potential combinatory strategies to improve immunotherapy outcomes in ovarian cancer patients.

Long Non-Coding RNAs: Bridging Cancer-Associated Thrombosis and Clinical Outcome of Ovarian Cancer Patients.

Ovarian cancer (OC) and venous thromboembolism (VTE) have a close relationship, in which tumour cells surpass the haemostatic system to drive cancer progression. Long non-coding RNAs (lncRNAs) have been implicated in VTE pathogenesis, yet their roles in cancer-associated thrombosis (CAT) and their prognostic value are unexplored. Understanding how these lncRNAs influence venous thrombogenesis and ovarian tumorigenesis may lead to the identification of valuable biomarkers for VTE and OC management. Thus, this study evaluated the impact of five lncRNAs, namely MALAT1, TUG1, NEAT1, XIST and MEG8, on a cohort of 40 OC patients. Patients who developed VTE after OC diagnosis had worse overall survival compared to their counterparts (log-rank test, p = 0.028). Elevated pre-chemotherapy MEG8 levels in peripheral blood cells (PBCs) predicted VTE after OC diagnosis (Mann-Whitney U test, p = 0.037; Χ2 test, p = 0.033). In opposition, its low levels were linked to a higher risk of OC progression (adjusted hazard ratio (aHR) = 3.00; p = 0.039). Furthermore, low pre-chemotherapy NEAT1 levels in PBCs were associated with a higher risk of death (aHR = 6.25; p = 0.008). As for the remaining lncRNAs, no significant association with VTE incidence, OC progression or related mortality was observed. Future investigation with external validation in larger cohorts is needed to dissect the implications of the evaluated lncRNAs in OC patients.

Insulin-like growth factor 2 mRNA-binding protein 2 is a therapeutic target in ovarian cancer.

Ovarian cancer (OC) is a fatal gynecologic disease. The most common treatment for OC patients is surgery combined with chemotherapy but most patients at advanced stages eventually develop relapse due to chemoresistance. This study examined the role and function of insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) in OC. We observed that the expression of IGF2BP2 mRNA and protein was up-regulated in OC cells and tissues using quantitative real-time polymerase chain reaction (qRT-PCR) and western blot, respectively. An increase in IGF2BP2 expression at mRNA and protein levels was verified by the analyses of The Cancer Genome Atlas (TCGA) and Clinical Proteomic Tumor Analysis Consortium (CPTAC), respectively. Gene Expression Omnibus (GEO) and Cancer Cell Line Encyclopedia (CCLE) databases were applied to analyze the expression and clinical value of IGF2BP2. Gene set enrichment analysis (GSEA), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Ontology (GO) analyses explored biological functions and the involvement of IGF2BP2 in cell growth. Indeed, the knockdown of IGF2BP2 resulted in the inhibition of OC cell proliferation evaluated by the Cell Counting Kit-8 assay. Genomic amplification of IGF2BP2 partly accounted for its overexpression. High expression of IGF2BP2 was associated with signal transducer and activator of transcription 1 (STAT1) and drug sensitivity and was correlated with an unfavorable survival outcome in OC patients. Furthermore, the responsiveness of chemotherapy and immunotherapy were analyzed using the "pRRophetic" R package and The Cancer Immune Atlas (TCIA) database, respectively. The low expression of IGF2BP2 was associated with chemoresistance but with high tumor microenvironment scores and tumor-infiltrating immune cells, suggesting that immunotherapy may apply in chemoresistant patients. The alteration of IGF2BP2 expression may respond to chemotherapy and immunotherapy. Thus, IGF2BP2 shows potential as a therapeutic target and diagnostic biomarker for OC.

Metabolic and senescence characteristics associated with the immune microenvironment in ovarian cancer.

Ovarian cancer is a highly malignant gynecological cancer influenced by the immune microenvironment, metabolic reprogramming, and cellular senescence. This review provides a comprehensive overview of these characteristics. Metabolic reprogramming affects immune cell function and tumor growth signals. Cellular senescence in immune and tumor cells impacts anti-tumor responses and therapy resistance. Targeting immune cell metabolism and inducing tumor cell senescence offer potential therapeutic strategies. However, challenges remain in identifying specific targets and biomarkers. Understanding the interplay of these characteristics can lead to innovative therapeutic approaches. Further research is needed to elucidate mechanisms, validate strategies, and improve patient outcomes in ovarian cancer.

The prognostic and clinical value of neutrophil-to-lymphocyte ratio (NLR) in ovarian cancer: A systematic review and meta-analysis.

Ovarian cancer (OC) is a major gynecological malignancy with varying prognosis. The Neutrophil-toLymphocyte Ratio (NLR) has been proposed as a potential prognostic biomarker. This study aimed to evaluate the prognostic and clinical value of NLR in OC. A systematic review and meta-analysis were performed following PRISMA guidelines, including studies that evaluated the association between NLR and survival outcomes in OC patients. Search was performed in PubMed, Embase, Web of Science, and Cochrane Library databases. Quality assessment was done using Newcastle-Ottawa Scale (NOS). Heterogeneity was assessed, and pooled hazard ratios (HRs) were calculated using fixed or random-effects models as appropriate.

Machine learning developed a PI3K/Akt pathway-related signature for predicting prognosis and drug sensitivity in ovarian cancer.

Ovarian cancer is one of the deadliest malignancies among females, generally having a poor prognosis. The PI3K/Akt pathway plays a vital role in the oncogenesis and progression of many types of cancer. Limited studies have fully clarified the role of PI3K/Akt pathway in the prognosis of ovarian cancer and its correlation with drug sensitivity. A prognostic PI3K/Akt pathway related signature (PRS) was constructed with 10 machine learning algorithms using TCGA, GSE14764, GSE26193, GSE26712, GSE63885 and GSE140082 datasets. Gaussian mixture and logistic regression were performed to identify the optimal models for classifying lymphatic and venous invasion. The optimal prognostic PRS developed by Lasso + survivalSVM algorithm acted as an independent risk factor for overall survival (OS) of ovarian cancer patients and had a good performance in evaluating OS rate of ovarian cancer patients. Significant correlation was obtained between PRS-based risk score and Immune score, ESTIMATE score, immune cells and cancer-related hallmarks. Low risk score indicated a lower immune escape score, TIDE score, and higher PD1&CTLA4 immunophenoscore in ovarian cancer. Moreover, PRS-based risk score acted as an indicator for drug sensitivity in the immunotherapy and chemotherapy of ovarian cancer patients. All in all, our study developed a prognostic PRS showing powerful and good performance in predicting clinical outcome of ovarian cancer patients. PRS could serve as an indicator for drug sensitivity in the chemotherapy and immunotherapy.

Gene expression of non-homologous end-joining pathways in the prognosis of ovarian cancer

Ovarian cancer is the deadliest gynecologic malignancy in women, with a 46% five-year overall survival rate. The objective of the study was to investigate the effects of non-homologous end-joining (NHEJ) genes on clinical outcomes of ovarian cancer patients. To determine if these genes act as prognostic biomarkers of mortality and disease progression, the expression profiles of 48 NHEJ-associated genes were analyzed using an array of statistical and machine learning techniques: logistic regression models, decision trees, naive-Bayes, two sample t-tests, support vector machines, hierarchical clustering, principal component analysis, and neural networks. In this process, the correlation of genes with patient survival and disease progression and recurrence was noted. Also, multiple features from the gene set were found to have significant predictive capabilities. APTX, BRCA1, PAXX, LIG1, and TP53 were identified as most important out of all the candidate genes for predicting clinical outcomes of ovarian cancer patients.

KLF5 Promotes Tumor Progression and Parp Inhibitor Resistance in Ovarian Cancer.

One major characteristic of tumor cells is the aberrant activation of epigenetic regulatory elements, which remodelthe tumor transcriptome and ultimately promotecancer progression and drug resistance. However, the oncogenic functions and mechanisms of ovarian cancer (OC) remain elusive. Here, super-enhancer (SE) regulatory elements that are aberrantly activated in OC are identified and it is found that SEs drive the relative specific expression of the transcription factor KLF5 in OC patients and poly(ADP-ribose) polymerase inhibitor (PARPi)-resistant patients. KLF5 expression is associated with poor outcomes in OC patients and can drive tumor progression in vitro and in vivo. Mechanistically, KLF5 forms a transcriptional complex with EHF and ELF3 and binds to the promoter region of RAD51 to enhance its transcription, strengthening the homologous recombination repair (HRR) pathway. Notably, the combination of suberoylanilide hydroxamic acid (SAHA) and olaparib significantly inhibits tumor growth and metastasis of PARPi-resistant OC cells with high KLF5. In conclusion, it is discovered that SEs-driven KLF5 is a key regulatory factor in OC progression and PARPi resistance;and potential therapeutic strategies for OC patients with PARPi resistance and high KLF5 are identified.

Does the diagnostic timing of cancer-associated thromboembolism influence the survival outcome in ovarian cancer patients?

Efforts were made to explore the influence of diagnostic timing for cancer-associated thromboembolic events on survival of ovarian cancer patients. We reviewed the medical records of 75 ovarian cancer patients with thromboembolism and evaluated the prognostic factors affecting disease-free survival and overall survival. These 75 patients were classified into two categories by the diagnostic timing of the thromboembolism, during (33 cases) and after (42 cases) initial diagnosis of ovarian cancer groups. The diagnostic timing of thromboembolism was not related to disease-free survival or overall survival of the studied population. Advanced disease stage, clear cell histology, interval debulking surgery, no recurrence/persistence of ovarian cancer, and patients treated with anticoagulant(s) treatment >3 months were associated with the disease-free survival. Advanced disease stage, clear cell histology, body mass index (BMI) ≥24kg/m2 at the diagnosis of ovarian cancer, and no recurrence/persistence of ovarian cancer influenced the overall survival. In the subgroup analysis, compared to the after initial ovarian cancer diagnosis group, patients with stage I/II disease, BMI <24kg/m2 at the diagnosis of ovarian cancer, or primary debulking surgery in the during cancer diagnosis group had longer disease-free survival, and overall survival benefit was observed in cases with stage I/II disease, or primary debulking surgery. The diagnostic timing of thromboembolism was not related to disease-free or overall survival of ovarian cancer patients, but associated with that of specific patient subgroups.

Timing of interval debulking surgery and postoperative chemotherapy after neoadjuvant chemotherapy in advanced epithelial ovarian cancer: a multicenter real-world study

BackgroundTo investigate the prognostic relevance of the time to interval debulking surgery (TTS) and the time to postoperative adjuvant chemotherapy (TTC) after the completion of neoadjuvant chemotherapy (NACT).MethodsA retrospective real-word study included 658 patients with histologically confirmed advanced epithelial ovarian cancer who received NACT at seven tertiary hospitals in China from June 2008 to June 2020. TTS was defined as the time interval from the completion of NACT to the time of interval debulking surgery (IDS). TTC was defined as the time interval from the completion of NACT to the initiation of postoperative adjuvant chemotherapy (PACT).ResultsThe median TTS and TTC were 25 (IQR, 20–29) and 40 (IQR, 33–49) days, respectively. Patients with TTS > 25 days were older (55 vs. 53 years, P = 0.012) and received more NACT cycles (median, 3 vs. 2, P = 0.002). Similar results were observed in patients with TTC > 40 days. In the multivariate analyses, TTS and TTC were not associated with PFS when stratified by median, quartile, or integrated as continuous variables (all P > 0.05). However, TTS and TTC were significantly associated with worse OS when stratified by median (P = 0.018 and 0.018, respectively), quartile (P = 0.169, 0.014, 0.027 and 0.012, 0.001, 0.033, respectively), or integrated as continuous variables (P = 0.018 and 0.011, respectively). Similarly, increasing TTS and TTC intervals were associated with a higher risk of death (Ptrend = 0.016 and 0.031, respectively) but not with recurrence (Ptrend = 0.103 and 0.381, respectively).ConclusionThe delays of IDS and PACT after the completion of NACT have adverse impacts on OS but no impacts on PFS, which indicates that reducing delays of IDS and PACT might ameliorate the outcomes of ovarian cancer patients treated with NACT.

PSMD8 can serve as potential biomarker and therapeutic target of the PSMD family in ovarian cancer: based on bioinformatics analysis and in vitro validation

BackgroundThe ubiquity-proteasome system is an indispensable mechanism for regulating intracellular protein degradation, thereby affecting human antigen processing, signal transduction, and cell cycle regulation. We used bioinformatics database to predict the expression and related roles of all members of the PSMD family in ovarian cancer. Our findings may provide a theoretical basis for early diagnosis, prognostic assessment, and targeted therapy of ovarian cancer.MethodsGEPIA, cBioPortal, and Kaplan–Meier Plotter databases were used to analyze the mRNA expression levels, gene variation, and prognostic value of PSMD family members in ovarian cancer. PSMD8 was identified as the member with the best prognostic value. The TISIDB database was used to analyze the correlation between PSMD8 and immunity, and the role of PSMD8 in ovarian cancer tissue was verified by immunohistochemical experiments. The relationship of PSMD8 expression with clinicopathological parameters and survival outcomes of ovarian cancer patients was analyzed. The effects of PSMD8 on malignant biological behaviors of invasion, migration, and proliferation of ovarian cancer cells were studied by in vitro experiments.ResultsThe expression levels of PSMD8/14 mRNA in ovarian cancer tissues were significantly higher than those in normal ovarian tissues, and the expression levels of PSMD2/3/4/5/8/11/12/14 mRNA were associated with prognosis. Up-regulation of PSMD4/8/14 mRNA expression was associated with poor OS, and the up-regulation of PSMD2/3/5/8 mRNA expression was associated with poor PFS in patients with ovarian serous carcinomas. Gene function and enrichment analysis showed that PSMD8 is mainly involved in biological processes such as energy metabolism, DNA replication, and protein synthesis. Immunohistochemical experiments showed that PSMD8 was mainly expressed in the cytoplasm and the expression level was correlated with FIGO stage. Patients with high PSMD8 expression had poor prognosis. Overexpression of PSMD8 significantly enhanced the proliferation, migration, and invasion abilities in ovarian cancer cells.ConclusionWe observed different degrees of abnormal expression of members of PSMD family in ovarian cancer. Among these, PSMD8 was significantly overexpressed in ovarian malignant tissue, and was associated with poor prognosis. PSMDs, especially PSMD8, can serve as potential diagnostic and prognostic biomarkers and therapeutic targets in ovarian cancer.

Targeting regeneration capacity of stem cells to improve surgical wound healing outcomes in ovarian cancer patients.

e17578 Background: Despite advancements in care and treatment, ovarian cancer continues to be a challenging and deadly disease. Currently, standard treatment comprises a combination of cytoreductive surgery, often followed by platinum-based chemotherapy, known to negatively affect wound healing recovery. Therefore, achieving optimal post-surgical wound healing is critical in preventing delays in treatment, which can greatly impact patient outcomes and overall survival. Adipose-derived stem cells (ASC) have been shown to be crucial in regeneration of tissue and wound closure, as well as in regulating inflammatory differentiation and proliferation processes. Thus, improving the regeneration capacity of ASCs in wounds may speed post-surgical recovery and subsequent treatments. While a number of compounds have been shown to potentiate the regeneration ability of ASCs, we hypothesize that naturally derived epigenetic compounds with anti-cancer properties (I3C and EGCG), as well as anti-inflammatory compounds (non-psychoactive cannabidiol, CBD), may have a role in increasing regeneration capacity of stem cells. Therefore, ASCs were primed with these compounds and expression of major inflammatory, anti-inflammatory, proliferation and regeneration markers was evaluated. Methods: ASCs were primed with either I3C 50uM, EGCG 10 uM, or CBD 100nM. Conditioned medium from these treatments was collected and underwent a protein array assay for detection of levels of 40 human inflammatory markers and cytokines according to the manufacturer instructions. A one-way ANOVA test and Tukey post-hoc testing analyzed intensities for each marker between the control group and each of the primed groups. Results: Our results indicate that ASCs primed with our epigenetic treatments significantly decrease expression of a multitude of inflammatory markers and cytokines. I3C primed ASCs showed significantly decreased expression of the following factors: I-309, IL-11, IL-12 p40, IL-12p70, IL-1α, IL-6sR, M-CSF, MIG, MIP-1α, MIP-1β, MIP-1δ, IL-6, MCP-1, TIMP-2. EGCG primed ASCs significantly decreased expression of IL-12p70, IL-13, IL-6sR, MIP-1α, MIP-1δ, RANTES, IL-6, IL-8, MCP-1, TIMP-2. CBD primed ASCs significantly decreased expression of IL-6. A p&lt; .05 was used. Conclusions: Priming ASCs with EGCG, I3C and CBD significantly down-regulate expression of a number of pro-inflammatory markers known to delay and interfere with the kinetics of wound healing processes, including wound inflammation, closure and scar formation. Therefore, these results suggest that naturally derived epigenetic compounds and CBD successfully potentiated ASCs’ ability to attenuate inflammation and wound healing processes. Consequently, our findings can lead to new diet and surgical ASC protocols which could optimize cancer post-operative wound healing closure time while decreasing inflammation.

Triple checkpoint blockade, but not anti-PD1 alone, enhances the efficacy of engineered adoptive T cell therapy in advanced ovarian cancer

Abstract Less than 50% of ovarian cancer patients survive five years after diagnosis. This rate has changed little in the last 30 years, highlighting the need for novel therapies. A promising strategy employs T cells engineered to target tumor-expressed proteins. Mesothelin (Msln) is overexpressed in ovarian cancers, contributes to the malignant and invasive phenotype and has limited expression in healthy cells, making it a candidate immunotherapy target. We used the immune-competent ID8 VEGFmouse model of advanced ovarian cancer to show that T cells engineered to express a Msln-specific T cell receptor (TCR Msln) can preferentially accumulate within established tumors, delay tumor growth and significantly prolong mouse survival. However, elements in the tumor microenvironment limited engineered T cell function. Tumor-bearing mice were therefore treated with TCR MslnT cells plus PD1, Tim-3 and/or Lag-3 checkpoint-blocking antibodies, alone or in combination. Triple checkpoint blockade, but not single- or double-agent treatments, dramatically increased effector cytokine production by intratumoral TCR MslnT cells. Single cell RNA-sequencing revealed gene expression changes in intratumoral TCR MslnT cells and myeloid cells consistent with immune activation and inflammation. Moreover, combining adoptive immunotherapy with triple checkpoint blockade prolonged survival in treated mice, relative to TCR Mslnwith or without single- or double-agent checkpoint blockade. These results suggest that disrupting multiple immune-inhibitory pathways simultaneously, which can be more safely pursued in a cell intrinsic form through genetic engineering, may be necessary to improve outcomes for ovarian cancer patients.