Survival Rate Of Ovarian Cancer Research Articles

Design of PI3K-mTOR Dual Inhibitors for Ovarian Cancer: Are We on the Right Track?

Ovarian cancer is one of the most familiar kinds of gynecological cancer seen in women. Though it is not as familiar as breast cancer, the survival rate for ovarian cancer is very low when compared with breast cancer. Even after being one among the familiar types, to date, there are no proper treatments available for ovarian cancer. All the treatments that are present currently show a high rate of recurrence after the treatment. Therefore, treating this silent killer from the roots is the need of the hour. PI3K/AKT/m- TOR pathway is one of the pathways that get altered during ovarian cancer. Studies are already going on for the inhibition of PI3K and mTOR separately. Efforts have been made to inhibit either PI3K or mTOR separately earlier. However, due to its side effects and resistance to the treatments available, current studies are based on the inhibition of PI3K and mTOR together. Inhibition of PI3K and mTOR simultaneously reduces the chances of negative feedback, thus decreasing the toxicity. This review contains the evolution of PI3K and mTOR drugs that are approved by the FDA and are in the trials for different cancer types, including Ovarian cancer. In this article, how a molecular targeted therapy can be made successful and free from toxicity for treating ovarian cancer is discussed. Therefore, this review paves the way for finding an effective scaffold rather than the clinical part. The scaffold thus selected can be further modified and synthesized in the future as dual PI3K/mTOR inhibitors specifically for OC.

ASSOCIATION OF VITAMIN D SERUM LEVELS AND OVARIAN CANCER : A SYSTEMATIC REVIEW

Background: Knowing the modifiable risk factors for prevention and improved prognosis is crucial, as the prognosis of ovarian cancer is poor and there are few population-level interventions for early identification and long-term therapeutic success. Research on cancer has shown a great deal of scientific interest in vitamin D since it may be one of these factors. Aims : This systematic review is to review the association of vitamin D serum levels in patients with ovarian cancer Methods: By comparing itself to the standards set by the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) 2020, this study was able to show that it met all of the requirements. So, the experts were able to make sure that the study was as up-to-date as it was possible to be. For this search approach, publications that came out between 2014 and 2024 were taken into account. Several different online reference sources, like Pubmed and SCIENCE DIRECT, were used to do this. It was decided not to take into account review pieces, works that had already been published, or works that were only half done. Result: In the PubMed database, the results of our search brought up 329 articles, whereas the results of our search on SCIENCE DIRECT brought up 298 articles. The results of the search conducted for the last year of 2014 yielded a total 8 articles for PubMed and 12 articles for SCIENCE DIRECT. In the end, we compiled a total of 4 papers, 3 of which came from PubMed and 1 of which came from SCIENCE DIRECT. We included four research that met the criteria. Conclusion: In summary, some of the studies showed vitamin D supplementation is not necessary to increase the survival rate of ovarian cancer in the absence of a vitamin D shortage. There are limited studies about the association of vitamin D and ovarian cancer.

Selectively targeting BCL6 using a small molecule inhibitor is a potential therapeutic strategy for ovarian cancer.

Ovarian cancer is one of the tumors with the highest fatality rate among gynecological tumors. The current 5-year survival rate of ovarian cancer is <35%. Therefore, more novel alternative strategies and drugs are needed to treat ovarian cancer. The transcription factor B-cell lymphoma 6 (BCL6) is critically associated with poor prognosis and cisplatin resistance in ovarian cancer treatment. Therefore, BCL6 may be an attractive therapeutic target for ovarian cancer. However, the role of targeting BCL6 in ovarian cancer remains elusive. Here, we developed a novel BCL6 small molecule inhibitor, WK369, which exhibits excellent anti-ovarian cancer bioactivity, induces cell cycle arrest and causes apoptosis. WK369 effectively inhibits the growth and metastasis of ovarian cancer without obvious toxicity in vitro and in vivo. meanwhile, WK369 can prolong the survival of ovarian cancer-bearing mice. It is worth noting that WK369 also has significant anti-tumor effects on cisplatin-resistant ovarian cancer cell lines. Mechanistic studies have shown that WK369 can directly bind to the BCL6-BTB domain and block the interaction between BCL6 and SMRT, leading to the reactivation of p53, ATR and CDKN1A. BCL6-AKT, BCL6-MEK/ERK crosstalk is suppressed. As a first attempt, our study demonstrates that targeting BCL6 may be an effective approach to treat ovarian cancer and that WK369 has the potential to be used as a candidate therapeutic agent for ovarian cancer.

Sol-gel synthesis and cytotoxicity evaluation of selenium-doped cerium oxide nanoparticles for biomedical applications.

Over the past few years, ovarian cancer is the second most commonly diagnosed cancer among women. Despite the widespread knowledge of its prevalence, the curative measures and survival rates for ovarian cancer have not improved significantly, making it a challenging condition. Nanotechnology has become increasingly prominent in the field of cancer treatment. Previous studies showed both cerium oxide nanoparticles (CONPs) and selenium (Se) had anti-cancer. Therefore, doping selenium into CONPs may exhibit a more significant anti-cancer effect on ovarian cancer cells. Cerium nitrate hexahydrate, sodium selenite, and gelatin were employed for the production of CONPs and Se-doped CONPs. The EDX, XRD, and TEM/PSA imaging were employed to investigate the structural characteristics and morphology of the synthesized Se-doped CONPs. The reactive oxygen species (ROS) level and TNF, IL-6, and IL-1B gene expression were evaluated after inoculating A2780 human epithelial ovarian carcinoma (HEOC) with Se-doped CONP. Statistical analysis was conducted using ANOVA, followed by Bonferroni's t-test for multiple group comparisons. Se-doped CONPs had IC50 of 113 and 49 PPM after 24 and 48 h, respectively. In addition, Se-doped CONPs with concentrations of 50 and 100 PPM significantly reduced to ROS levels in the HEOC cell line. Also, 50 and 100 PPM Se-doped CONPs lead to significantly reduced TNF, IL-6, and IL-1B gene expression compared to the control group in the HEOC cell line. Our study showed the potential anti-cancer effects of Se-doped CONPs on ovarian cancer cell lines.

A macrophage related signature for predicting prognosis and drug sensitivity in ovarian cancer based on integrative machine learning

BackgroundOvarian cancer ranks the leading cause of gynecologic cancer-related death in the United States and the fifth most common cause of cancer-related mortality among American women. Increasing evidences have highlighted the vital role of macrophages M2/M1 proportion in tumor progression, prognosis and immunotherapy.MethodsWeighted gene co-expression network analysis (WGCNA) was performed to identify macrophages related markers. Integrative procedure including 10 machine learning algorithms were performed to develop a prognostic macrophage related signature (MRS) with TCGA, GSE14764, GSE140082 datasets. The role of MRS in tumor microenvironment (TME) and therapy response was evaluated with the data of CIBERSORT, MCPcounter, QUANTISEQ, XCELL, CIBERSORT-ABS, TIMER and EPIC, GSE91061 and IMvigor210 dataset.ResultsThe optimal MRS developed by the combination of CoxBoost and StepCox[forward] algorithm served as an independent risk factor in ovarian cancer. Compared with stage, grade and other established prognostic signatures, the current MRS had a better performance in predicting the overall survival rate of ovarian cancer patients. Low risk score indicated a higher TME score, higher level of immune cells, higher immunophenoscore, higher tumor mutational burden, lower TIDE score and lower IC50 value in ovarian cancer. The survival prediction nomogram had a good potential for clinical application in predicting the 1-, 3-, and 5-year overall survival rate of ovarian cancer patients.ConclusionAll in all, the current study constructed a powerful prognostic MRS for ovarian cancer patients using 10 machine learning algorithms. This MRS could predict the prognosis and drug sensitivity in ovarian cancer.

Metabolism-related gene vaccines and immune infiltration in ovarian cancer: A novel risk score model of machine learning.

The present study aims to develop a metabolic gene signature to evaluate the survival rate of ovarian cancer (OC) patients and analyze the potential mechanisms of metabolic genes in OC because the difficulty in early detection of OC often leads to poor treatment outcomes. A non-negative matrix factorization algorithm was applied to determine molecular subtypes according to metabolism genes. To build a risk prognosis model, least absolute shrinkage and selection operator multivariate Cox analysis was carried out with weighted correlation network analysis (WCGNA). Glycolytic flux and mitochondrial function were evaluated by conducting seahorse analysis. On the basis of metabolism-related genes, the two subtypes of OC samples present in The Cancer Genome Atlas database were distinguished. An analysis of WGCNA identified 1056 genes. Lastly, a 10-gene signature (CMAS, ADH1B, PLA2G2D, BHMT, CACNA1C, AADAC, ALOX12, CYP2R1, SCN1B and ME1) was constructed that demonstrated promising performance in predicting outcome in patients with OC. The RiskScore of the gene signature was linked to microenvironment cell infiltration and immune checkpoint. Higher RiskScores were associated with poorer results for OC patients. Seahorse analysis shows the influence of CMAS in cell energy metabolism. In the present study, a novel marker for evaluating the survival of OC patients was developed through the creation of a gene signature incorporating metabolism-related genes. Our knowledge of immunotherapy and microenvironment cell infiltration may be enriched by evaluating metabolism-related gene modification patterns.

Survival rate of ovarian cancer in Asian countries: a systematic review and meta-analysis

BackgroundOvarian cancer is amongst one of the most commonly occurring cancers affecting women, and the leading cause of gynecologic related cancer death. Its poor prognosis and high mortality rates can be attributed to the absence of specific signs and symptoms until advance stages, which frequently leads to late diagnosis. Survival rate of patients diagnosed with ovarian cancer can be used in order to better assess current standard of care; the aim of this study is to evaluate the survival rate of ovarian cancer patients in Asia.MethodsSystematic review was performed on articles that were published by the end of August 2021 in five international databases, including Medline / PubMed, ProQuest, Scopus, Web of Knowledge, and Google Scholar. The Newcastle-Ottawa quality evaluation form was used for cohort studies to evaluate the quality of the articles. The Cochran-Q and I2 tests were used to calculate the heterogeneity of the studies. The Meta-regression analysis was also done according to when the study was published.ResultsA total of 667 articles were reviewed, from which 108 were included in this study because they passed the criteria. Based on a randomized model, the survival rates of ovarian cancer after 1, 3 and 5 years were respectively 73.65% (95% CI, 68.66–78.64), 61.31% (95% CI, 55.39–67.23) and 59.60% (95% CI, 56.06–63.13). Additionally, based on meta-regression analysis, there was no relationship between the year of study and survival rate.ConclusionsThe 1-year survival rate was higher than that of 3- and 5-year for ovarian cancer. This study provides invaluable information that can not only help establish better standard of care for treatment of ovarian cancer, but also assist in development of superior health interventions for prevention and treatment of the disease.

Cascade genetic testing (CGT) female first-degree relatives (FDR) of men with germline BRCA2 mutations (gBRCA2mut) and prostate cancer (PCa): A cost-effectiveness analysis.

e17099 Background: g BRCA2mut are associated with increased risk of PCa, breast cancer (BC), and ovarian cancer (OC). ~5% of men with metastatic PCa have g BRCA2mut. CGT is recommended for their relatives as there are implications for cancer prevention and early detection strategies. Little is known about CGT initiated by men with PCa. Here we evaluate the cost-effectiveness of CGT in FDR of men with PCa and g BRCA2mut. Methods: A decision-analytic model was created with TreeAge software to compare BC and OC outcomes for female FDRs who underwent CGT for g BRCA2mut versus no CGT. Our theoretical cohort contained 100,000 females, a conservative estimate of patients who could benefit from CGT. We used literature derived estimates to determine the percentage of patients that would pursue risk-reducing mastectomy, risk-reducing salpingo-oophorectomy, both surgeries, or surveillance after CGT. Outcomes included BC or OC diagnoses, survivorship, and cancer death. We derived all probabilities, costs, utilities, and life expectancies from the literature and discounted quality adjusted life years (QALYs) at a rate of 3%. Incremental cost-effectiveness (ICER) was calculated to determine the cost per QALY gained and set the willingness-to-pay threshold at $100,000/QALY. We assessed the robustness of the model with sensitivity analyses. Results: In our theoretical cohort, CGT of female FDRs resulted in 12,910 less BC diagnoses and 6,360 less BC deaths. CGT was associated with lower BC death rates (26.1%) compared to no CGT (35.8%). OC survival rates were higher with CGT (73.1%) compared to no CGT (36.4%). Our model resulted in lower costs and higher QALYs (a dominant strategy) among the CGT cohort with an ICER of -$7,211.40 per QALY, saving an estimated $595 million. We found that CGT in females was the dominant strategy in 100% of the samples, once uncertainty was incorporated into our model inputs via Monte Carlo simulation. The cost-effectiveness of CGT for male FDRs will be presented at the meeting. Conclusions: In this study, CGT of female FDRs of men with PCa and g BRCA2mut was the dominant strategy to improve BC and OC outcomes, including increased survivorship and reduced BC and OC development. CGT was associated with reduced costs and increased QALYs. CGT for female FDRs of patients with PCa and g BRCA2mut may be a cost-effective approach for identifying and informing individuals with potentially harmful mutations. [Table: see text]

Association of Physician Densities and Gynecologic Cancer Outcomes in the United States

ABSTRACT Gynecologic cancers account for approximately 94,000 new cancer diagnosis yearly in the United States, with prognosis largely dependent on stage at diagnosis, sociodemographic, geographic, and other biological factors. Proximity to gynecologic oncologists has been shown to improve cancer outcomes; however, it remains unclear whether physician density of nonsubspecialists such as obstetrician-gynecologists (OBGYNs) or primary care physicians (PCPs) has a similar benefit. The aim of this study was to determine whether there is a correlation between the density of OBGYNs and PCPs with outcomes of patients with gynecologic cancer at the county level in the United States. County-level oncologic and sociodemographic data on cases between 2005 and 2018 were obtained from the Surveillance, Epidemiology, and End Results (SEER) Research Plus database. Female population by county was collected from the United States Census Bureau and physician density information from the Area Health Resources File. Backward stepwise linear regression was performed for both AJCC cancer stage at diagnosis and 5-year survival rate while accounting for county-level sociodemographic factors. A total of 113,938 patients were included in the analysis for AJCC stage at diagnosis and 98,573 for 5-year survival rate. Across all cancer types, the average density was 18 and 114 OBGYNs and PCPs per 100,000 females in metropolitan areas, respectively, whereas the average density was 8 and 89 OBGYNs and PCPs per 100,000 females in nonmetropolitan areas, respectively. Increasing PCP density was associated with an earlier stage at diagnosis for cervical cancer (95% CI, −6.27 to −0.05; P &lt; 0.05), even after adjusting for sociodemographic factors. No correlation between OBGYN density and cervical cancer stage at diagnosis was found. After adjusting for county-level sociodemographic factors, increasing median household income was associated with an earlier stage at diagnosis for cervical cancer (P = 0.01) and increasing percentage of Black females was associated with a later stage at diagnosis for uterine cancer (P &lt; 0.01). Increasing PCP density was associated with an increased 5-year survival rate for cervical cancer (95% CI, 0.03–0.09; P &lt; 0.05). After adjustment for sociodemographic factors, no correlation between OBGYN density and cervical cancer survival was observed, nor was any correlation between PCP or OBGYN density and 5-year survival rate by stage for either endometrial or ovarian cancer. After adjustment for county-level sociodemographic factors, an increasing percentage of those with a bachelor’s degree was associated with an increased 5-year survival in cervical cancer (P &lt; 0.01), an increasing percentage of Black females was associated with a decreased 5-year survival rate for uterine cancer (P &lt; 0.01), and increasing median household income was associated with an increased 5-year survival rate for ovarian cancer (P &lt; 0.01). The results of this study suggest that only cervical cancer outcomes are significantly correlated with PCP density at the county level, possibly because cervical cancer is the only gynecologic cancer with recommended routine screening guidelines.

The Challenges and Prospects of p53-Based Therapies in Ovarian Cancer.

It has been well established that mutations in the tumor suppressor gene, p53, occur readily in a vast majority of cancer tumors, including ovarian cancer. Typically diagnosed in stages three or four, ovarian cancer is the fifth leading cause of death in women, despite accounting for only 2.5% of all female malignancies. The overall 5-year survival rate for ovarian cancer is around 47%; however, this drops to an abysmal 29% for the most common type of ovarian cancer, high-grade serous ovarian carcinoma (HGSOC). HGSOC has upwards of 96% of cases expressing mutations in p53. Therefore, wild-type (WT) p53 and p53-based therapies have been explored as treatment options via a plethora of drug delivery vehicles including nanoparticles, viruses, polymers, and liposomes. However, previous p53 therapeutics have faced many challenges, which have resulted in their limited translational success to date. This review highlights a selection of these historical p53-targeted therapeutics for ovarian cancer, why they failed, and what the future could hold for a new generation of this class of therapies.

Oncolytic adenovirus with MUC16-BiTE shows enhanced antitumor immune response by reversing the tumor microenvironment in PDX model of ovarian cancer

ABSTRACT The improved survival rate of ovarian cancer (OC) is related to the action of infiltrating cytotoxic T lymphocytes (CTLs). Recently, oncolytic adenoviruses (OAds) have emerged as a key player in treating solid tumors; however, the immunosuppressive tumor microenvironment (TME) and the body-mediated antiviral immune response limit their therapeutic effect. In this study, we tested the hypothesis that bispecific T-cell engagers (BiTEs) could activate and redirect CTLs to increase the anti-tumor effect of OAds. We modified the parental OAd to express a MUC16-targeting BiTE antibody (OAd-MUC16-BiTE), which retained its oncolytic properties and replication ability in vitro. This BiTE secreted from infected tumor cells into the microenvironment binds to MUC16 on target cells and cross‐links them to CD3 on T cells, leading to activation, proliferation, and toxicity of T cells against MUC16+ tumor cells. In cell coculture assays, OAd-MUC16-BiTE–mediated oncolysis enhanced T-cell–mediated tumor cell killing and bystander effect. In ex vivo tumor cultures freshly derived from OC patients, OAd-MUC16-BiTE overcame the suppressed immune TME, achieving stronger toxicity than the parental virus. Moreover, in the cell-derived xenograft and patient-derived xenograft model, OAd-MUC16-BiTE showed stronger antitumor activity and increased the number of CTLs, compared with the parental virus. Further, we demonstrated that the OAd-MUC16-BiTE-mediated anti-tumor activity is related to the reversal of the TME and improved MHC I antigen presentation. Overall, our results show how arming OAds with BiTE can overcome limitations in oncolytic virotherapy, yielding a potent therapy that is ready for clinical assessment.

Abstract 192: Ex vivo screening and analysis of novel effective treatments for ovarian cancer

Abstract Purpose: Ovarian cancer is the most lethal gynecological cancer. Histologically, about 90% of the ovarian cancers have epithelial origin and more than 75% are characterized as high-grade serous ovarian cancer (HGSOC). Despite having a good primary response to the standard platinum-taxane based chemotherapy, almost all HGSOC patients experience a relapsed disease. The 5-year survival rate of ovarian cancer is only 38% globally, indicating need for the development of novel efficient treatments to fight the resistance. Here we have established a personalized drug screening and evaluation platform using HGSOC patient samples and medicines approved for treatment of different types of cancers. Methods: Tissues collected from ovarian cancer patients were grown as 3-dimensional (3D) ex vivo long-term tumor organoid cultures. Seven HGSOC cell lines were additionally grown as spheroids or as xenograft tumors to establish them as 3D tumor organoid cultures for drug efficiency evaluation. Cancer stemness and further classification of samples were determined via immunofluorescent staining with relevant antibodies (pax8, Ki67, acetylated tubulin, p53, cytokeratin-8) and consequent high-throughput imaging using the ImageXpress Micro Confocal microscope (Molecular Devices). The images were analyzed and quantified using MetaXpress software. Organoid growth and response to tested treatments was validated via invasive growth and survival assays. Both assays were used to monitor resistance of organoids towards cisplatin and carboplatin treatment and towards suggested potential new treatments. Cancer drugs were selected according to suggestions based on RNA seq, DNA and/or drug screenings done in cancer cell lines. A preclinical mouse model (in immunodeficient NOD/Shi-scid/IL-2Rγnull (NOG) mice) was set up to be used for in vivo validation by monitoring the tumor growth in response to the treatment. Results: Currently, 20 patient tumor samples received from Turku University Hospital, Finland (KH, JH) have been cultured in 4 different culture media to obtain highest possible survival rates for each sample. Organoids from ovarian cancer cell lines are characterized for their resistance to increasing concentrations of platinum treatment. Notably, organoid analysis protocols and screening conditions have been setup for the high-throughput microscopy. These include organoid growth, survival, and invasiveness/aggressiveness. We are currently set up for screening organoids with the first drugs suggested by bioinformatics-based genetic pathway analysis and drug screening studies in cancer cell lines. The results of the screen will be presented. This study is a part of a large EU-funded ovarian cancer project DECIDER (https://www.deciderproject.eu/). Citation Format: Aikaterini Skorda, Kaisa Huhtinen, Wojciech Senkowski, Krister Wennerberg, Sampsa Hautaniemi, Johanna Hynninen, Tuula Kallunki. Ex vivo screening and analysis of novel effective treatments for ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 192.

Abstract 5147: The prion-like protein doppel as a seurm biomarker for epithelial ovarian cancer

Abstract Ovarian cancer has a dire prognosis with an overall 5-year survival rate of ~40%, whereas stage III and IV has a survival rate of only 3-19%. Failure to detect early contributes highly to the poor survival rate of ovarian cancer. Thus, early detection of EOCs is likely to translate into mortality benefit. Two tests used clinically to detect ovarian cancer are serum cancer antigen-125 (CA-125) and transvaginal ultrasound. Both have limitations of specificity and sensitivity. CA-125 along with other biomarkers that are in clinical trials express both in the ovaries and serum of healthy females. Thus, the specific detection among cancer-free controls versus ovarian cancer cases remains highly variable. We hypothesize to assess the Doppel (PRND gene) as a serum biomarker in the detection of epithelial ovarian cancers (EOC) at the early stages. Doppel, a prion-like protein first identified in 1996, is known to express in testis and appears to regulate male fertility. Previously, we and others reported that Doppel is a highly specific tumor endothelium marker. In this study, to validate the potential of Doppel as an EOC serum biomarker, using ELISA, we detected Doppel concentration in the sera of 76 sera samples from patients with stage and histopathology information, and in 18 normal human sera (NHS). Doppel level was significantly higher in sera of EOC patients than NHS (0.720 vs 6.653 ng/ml, p&amp;lt;0.0001); 72 out of 76 patients were positive for Doppel expression (cut off value was calculated as Mean+3×SEM = 1.296 ng/mL) while only 3 out of 18 cases were positive for NHS. Receiver operating characteristic (ROC) analysis showed that Doppel can differentiate EOC patients from normal individuals with AUC of 0.957, sensitivity of 90.8%, and specificity of 90%. Doppel was markedly higher in all stages of EOC than NHS (Stage I, 6.261 ng/mL; Stage II, 8.045 ng/ml; Stage III, 7.040 ng/mL; and Stage IV, 5.726 ng/ml vs NHS 0.720 ng/ml; p&amp;lt;0.001). Interestingly, serum Doppel level was higher among EOC of serous adenocarcinoma (7.020 ng/mL; n = 39), mucinous (10.780 ng/mL; n = 8), and endometroid (7.295 ng/mL; n = 7) than clear cell (3.114 ng/mL; n = 7) or other types (4.855 ng/mL; n = 15). Together, our study showed the potential of Doppel as a serological biomarker for EOC detection. Citation Format: Xiaojun Zhang, Bowon Kang, Mazharul Karim, Jianying Zhang, Jae Yun Song, In-San Kim, Taslim A. Al-Hilal. The prion-like protein doppel as a seurm biomarker for epithelial ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5147.

Abstract 5148: Immune landscapes and interactions in human fallopian tubes and their implications for early high-grade serous ovarian cancers

Abstract The five-year survival rate of ovarian cancer (OC) dramatically rises from below 40% to 90% with patients who are diagnosed early (stage I), when the disease restricts to the ovary. Thus, the ultimate goals of our research are to learn how to detect ovarian cancer at its earliest stages of development and thereby improve patient survival and to learn how the immune microenvironment contributes to the development of OC. Achieving these goals requires us to better characterize the earliest steps in ovarian carcinogenesis. The human fallopian tube harbors the cell-of-origin for most high-grade serous 'ovarian' cancers (HGSOCs), but its cellular composition, particularly the immune component, is poorly characterized. Emerging evidence from several research groups using molecular sequencing technologies of fallopian tube epithelium strongly support this hypothesis. We recently described our use of single-cell transcriptome technology (scRNA-Seq) to profile the heterogeneity of non-malignant FT and define a novel transcriptional gene regulatory network of epithelial differentiation and tumorigenesis in the human FT. Here we present an in-depth characterization of the immune cell atlas for human fallopian tubes, which has not been reported. Our unpublished analyses of our FT dataset and the publicly available HGSOC scRNA-Seq dataset demonstrate a significant difference in the immune cell landscape. There are limited macrophages and a high abundance of monocytes in non-malignant FT and adjacent normal ovaries compared to those in HGSOC tumors. This finding leads us to hypothesize that the macrophage-to-monocyte ratio and their interactions with other immune cell types in human fallopian tubes create a permissive microenvironment allowing for the development of HGSOC and can provide a biomarker for early cancer detection. To test if those myeloid cells could be a marker for early HGSOC, we performed scRNA-seq on FT from women carrying mutant alleles of BRCA1 or BRCA2 who are at high risk of HGSOC. Intriguingly, the ratio of monocytes to macrophages in the FTs from half of these high-risk individuals is more like that found in HGSOC than in normal FT. Furthermore, computational analyses on myeloid cell types and their interactions with different epithelial cells, stromal fibroblast cells, and T and NK cells revealed the extended contribution of the non-epithelial microenvironment in FT, potentially driving early HGSOC development and progression. This cellular and molecular compendium of the human fallopian tube immune landscapes in cancer-free and cancer-high-risk women is expected to advance our understanding of the earliest stages of fallopian epithelial neoplasia. Citation Format: Josh Brand, Marcela Harro, Forough Abbasi, Xianzhi Lin, Matthew Siedhoff, Li Andrew, Bobbie J. Rimel, Fabiola Medeiros, Kate Lawrenson, Huy Q. Dinh. Immune landscapes and interactions in human fallopian tubes and their implications for early high-grade serous ovarian cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5148.

Early diagnostics and screening for ovarian cancer

Ovarian cancer is the sixth most common cancer in women. The overall 5-year survival rate for ovarian cancer is approximately 40% due to the fact that most cases are diagnosed at late stages. Detection of ovarian cancer at the earliest possible stages is a public health priority. The article provides a review of existing scientific data regarding the early detection and screening of ovarian cancer, based on an analysis of publications in international electronic databases. Screening strategies are most effective for detecting diseases in their early stages, but at the moment there is no standard instrumental method that could be recommended as a screening examination for detecting ovarian cancer at an early stage. In this regard, most researchers have switched to the field of biomarkers and their combinations. Currently, more than 200 tumor markers, which are produced with varying intensity in ovarian cancer, have been proposed, but only two of them, CA-125 and HE4, have been tested in clinical experience. The article highlights the role of new tumor markers, multimarker panels, longitudinal algorithms in the early diagnosis of ovarian cancer. Most of the studies on the early diagnosis of ovarian cancer is aimed at searching for new biomarkers or developing multimodal algorithms that include both tumor markers, free deoxyribonucleic acid, and ultrasound of the pelvic organs. However, there are still no convincing data on mortality reduction based on randomized controlled trials, which stops doctors from including one or another strategy for the early diagnosis of ovarian cancer in national protocols and/or recommendations as a screening examination.

The Role of SOD2 in Migration and Anchorage-Independent Growth of SKOV3 Ovarian Cancer Cells

The 5-year survival rates for ovarian cancer are 93%, 75%, and 30% for localized, regional, and distant tumors, respectively. These vast differences in survival rates underscore the need to identify novel therapeutic targets that are effective at different stages of tumor progression to better treat all patients diagnosed with this deadly disease.  Manganese superoxide dismutase (SOD2) is a mitochondrial antioxidant enzyme responsible for eliminating superoxide and preventing oxidative damage to the mitochondria. Recent studies have implicated changes in SOD2 expression levels in multiple cancers, including breast, colorectal, prostate, and head and neck. While studies have begun to unravel the role of SOD2 in ovarian cancer, no one has looked at the specific role SOD2 plays in distinct stages of tumor progression of ovarian cancer. Here, we report SOD2 deficiency (accomplished through utilizing shRNA techniques) results in increased invasive and migratory ability of SKOV3 cells, a commonly used ovarian adenocarcinoma cell line. In contrast, SOD2-deficient SKOV3 cells display abrogated anchorage-independent growth in soft agar. These studies in SKOV3 cells indicate that SOD2 expression hampers invasion and migration critical for early tumor initiation but helps maintain anchorage-independent growth necessary for ovarian cancer metastases. In aggregate, SOD2 plays a context-dependent role in ovarian cancer progression and its utility as a therapeutic target for later-stage anchorage-independent ovarian cancer cells should be further explored. (First online: March 1, 2022)

Chemerin promotes proliferation and migration of ovarian cancer cells by upregulating expression of PD-L1.

Ovarian cancer is the third-most-common malignant reproductive tumor in women. According to the American Cancer Society, it has the highest mortality rate of gynecological tumors. The five-year survival rate was only 29% during the period from 1975 to 2008 (Reid et al., 2017). In recent decades, the five-year survival rate of ovarian cancer has remained around 30% despite continuous improvements in surgery, chemotherapy, radiotherapy, and other therapeutic methods. However, because of the particularity of the volume and location of ovarian tissue, the early symptoms of ovarian cancer are hidden, and there is a lack of highly sensitive and specific screening methods. Most patients have advanced metastasis, including abdominal metastasis, when they are diagnosed (Reid et al., 2017). Therefore, exploring the mechanism of ovarian cancer metastasis and finding early preventive measures are key to improving the survival rate and reducing mortality caused by ovarian cancer.

Research Progress of Nectin-4 as a Targeted Therapy for Ovarian Cancer

Ovarian cancer is one of the most common gynecological malignancies. The 5-year survival rate of ovarian cancer is only 50%, which is considered to be the most lethal gynecologic malignant tumor.The high mortality of ovarian cancer patients can be attributed to chemotherapy resistance, extensive intraperitoneal metastasis and other factors.Tumor antigens are expressed on the surface of tumor cells and represent potential drug targets.One of the antigens is tumor associated nectin-4, which is a member of the immune globulin superfamily.This review highlights the role of nectin-4 as a therapeutic target for ovarian cancer, and discusses the relevant research data, which is an effective new direction in the treatment of ovarian cancer.Although there are still some challenges, targeted therapy is still a promising treatment for ovarian cancer.

LncRNA HOTTIP PROMOTES OVARIAN CANCER CELL INVASION AND METASTASIS BY STABILIZING HIF-1α IN THE ANOXIC CELLULAR MICROENVIRONMENT.

The high recurrence rate and low survival rate of ovarian cancer (OC) patients are closely related to an anoxic environment. We aim to study the mechanism of long non-coding RNA (lncRNA) HOXA transcript at the distal tip (HOTTIP) on hypoxia ovarian cancer cells (OCC) and its mechanism was investigated. Knockdown and overexpression of HOTTIP in human OCC (SKOV-3, OVCAR3) were performed. The expression levels of HOTTIP and HIF-1α were monitored by qRT-PCR and WB. Transwell was conducted to validate the cell migration and invasion. ELISA was performed to calculate VEGF concentration in cells. Cell viability was monitored by CCK-8. Cell apoptosis and cycle were tested by flow cytometry. RNA pull-down was used to analyze the interaction between HIF-1α and HOTTIP. HOTTIP was highly expressed in OCC. After HOTTIP knockdown, HIF-1α expression and VEGF concentration in OCC were decreased. Cell migration, invasion, and cell viability were decreased. Cell apoptosis rate and G0/G1 phase cells were increased. RNA pull-down indicated a direct interaction between HIF-1α and HOTTIP. HOTTIP formed a positive feedback loop with HIF-1α to promote the development and metastasis of hypoxia ovarian cancer. This study provided theoretical support for the development of new OC treatment strategies.

Identification of Hypoxia Signature to Assess the Tumor Immune Microenvironment and Predict Prognosis in Patients with Ovarian Cancer.

Background The 5-year overall survival rate of ovarian cancer (OC) patients is less than 40%. Hypoxia promotes the proliferation of OC cells and leads to the decline of cell immunity. It is crucial to find potential predictors or risk model related to OC prognosis. This study aimed at establishing the hypoxia-associated gene signature to assess tumor immune microenvironment and predicting the prognosis of OC. Methods The gene expression data of 378 OC patients and 370 OC patients were downloaded from datasets. The hypoxia risk model was constructed to reflect the immune microenvironment in OC and predict prognosis. Results 8 genes (AKAP12, ALDOC, ANGPTL4, CITED2, ISG20, PPP1R15A, PRDX5, and TGFBI) were included in the hypoxic gene signature. Patients in the high hypoxia risk group showed worse survival. Hypoxia signature significantly related to clinical features and may serve as an independent prognostic factor for OC patients. 2 types of immune cells, plasmacytoid dendritic cell and regulatory T cell, showed a significant infiltration in the tissues of the high hypoxia risk group patients. Most of the immunosuppressive genes (such as ARG1, CD160, CD244, CXCL12, DNMT1, and HAVCR1) and immune checkpoints (such as CD80, CTLA4, and CD274) were upregulated in the high hypoxia risk group. Gene sets related to the high hypoxia risk group were associated with signaling pathways of cell cycle, MAPK, mTOR, PI3K-Akt, VEGF, and AMPK. Conclusion The hypoxia risk model could serve as an independent prognostic indicator and reflect overall immune response intensity in the OC microenvironment.