Cause Of Gynecologic Cancer Death Research Articles

IRE1α inhibitor reduces cisplatin resistance in ovarian cancer by modulating IRE1α/XBP1 pathway.

Ovarian cancer, a leading cause of gynecological cancer deaths globally, poses significant treatment challenges. Cisplatin (CDDP) is the first treatment choice for ovarian cancer and it is initially effective. However, 80% of ovarian cancer patients eventually relapse and develop resistance, resulting in chemotherapy failure. Therefore, finding new treatment combinations to overcome ovarian cancer resistance can provide a new tactic to improve the ovarian cancer patients' survival rate. We first identified activation of the Unfolded Protein Response (UPR) in CDDP-resistant ovarian cancer cells, implicating the IRE1α/XBP1 pathway in promoting resistance. Our findings demonstrate that inhibiting IRE1α signaling can re-sensitizes resistant cells to CDDP in vivo and in vitro, suggesting that IRE1α inhibitor used in conjunction with CDDP presumably could merge as a novel therapeutic strategy. Here, our research highlights the critical role of IRE1α signaling in mediating CDDP resistance, and paves the way for improved treatment options through combinatorial therapy.

Brain Metastases from Ovarian Cancer: A Comprehensive Review

Ovarian Cancer Ovarian cancer (OC) is the current leading cause of gynecological cancer deaths. Despite its fatal outcome, only 20% of ovarian cancers are detected in the early stage. The reason involves a combination of factors — there is no reliable screening for ovarian cancer, and any symptoms of ovarian cancer tend to be vague and easily ignored. Consequently, OC is given the advantage of metastasizing due to ignorance. However, recently, overall survival from ovarian carcinoma has been reported to increase after improvements in treatment (Siegel et al., 2020). Brain Metastases from OC Central nervous system (CNS) metastasis from epithelial ovarian carcinoma (EOC) is uncommon, with an incidence of brain metastases ranging from 1–3% (Zumrut et al., 2020). Moreover, the treatment of brain metastases from ovarian carcinoma is currently ill-defined because of its rarity and the small affected population. The median survival after diagnosis of brain metastases was six months, meaning BMs mainly occurred while the patient was in stages III or VI of OC. Nevertheless, the median interval between diagnosis of ovarian carcinoma and consequent brain metastases is also quite long, approximately 2 years (Piura et al., 2011). However, neuro-cognition and quality of life across therapies are increasingly recognized as essential endpoints for patients as survival continues to increase. This paper is a comprehensive review of brain metastases from ovarian cancer, investigating tumour proliferation, metastatic mechanisms, the role of BRCA 1/2, and several therapy options, such as PARP inhibitors.

Tumorigenic role of Pak4 in ovarian cancer and its correlation with immune infiltration

BackgroundOvarian cancer is the most common cause of gynecological cancer death. Pak4 has been proved to be tumorigenic in many types of cancers, but its role in ovarian cancer is still not clarified.MethodsIn this study, we used immunohistochemistry to investigate into Pak4 expression in different histological types of ovarian cancer. TIMER, TISCH2, GEPIA, ualcan, KM plotter, GSCA and GeneMANIA were used to identify the prognostic roles and gene regulation networks of Pak4 in ovarian cancer. Immune infiltration levels were investigated using TIMER database.ResultsPak4 was highly expressed in ovarian cancers, regardless of different FIGO stages and histological grades. Single cell sequencing database proved that Pak4 was highly expressed in malignant ovarian cancer cells. Pak4 level was significantly correlated with different histological types of ovarian cancer. Pak4 expression was negatively connected with OS and PFS of ovarian cancer patients. Functions of Pak4 and its interacted genes were mainly involved in protein serine/threonine kinase activity, regulation of actin filament-based process and regulation of cytoskeleton organization. Pak4 level was negatively correlated with immune biomarkers of B cell infiltration (p = 2.39e-05), CD8 + T cell infiltration (p = 1.51e-04), neutrophil (p = 1.74e-06) and dendritic cell (p = 4.41e-08). Close correlation was found between Pak4 expression and T cell exhaustion (p < 0.05).ConclusionsOur results demonstrated the expression level, gene interaction networks and immune infiltration levels of Pak4 in ovarian cancer. And the results revealed role of Pak4 in tumorigenesis and the possibility to be a potential immunotherapeutic target.

Machine learning developed a fibroblast-related signature for predicting clinical outcome and drug sensitivity in ovarian cancer.

Ovarian cancer (OC) is the leading cause of gynecological cancer death. Cancer-associated fibroblasts (CAF) is involved in wound healing and inflammatory processes, tumor occurrence and progression, and chemotherapy resistance in OC. GSE184880 dataset was used to identify CAF-related genes in OC. CAF-related signature (CRS) was constructed using integrative 10 machine learning methods with the datasets from the Cancer Genome Atlas, GSE14764, GSE26193, GSE26712, GSE63885, and GSE140082. The performance of CRS in predicting immunotherapy benefits was verified using 3 immunotherapy datasets (GSE91061, GSE78220, and IMvigor210) and several immune calculating scores. The Lasso + StepCox[forward] method-based predicting model having a highest average C index of 0.69 was referred as the optimal CRS and it had a stable and powerful performance in predicting clinical outcome of OC patients, with the 1-, 3-, and 5-year area under curves were 0.699, 0.708, and 0.767 in the Cancer Genome Atlas cohort. The C index of CRS was higher than that of tumor grade, clinical stage, and many developed signatures. Low CRS score demonstrated lower tumor immune dysfunction and exclusion score, lower immune escape score, higher PD1&CTLA4 immunophenoscore, higher tumor mutation burden score, higher response rate and better prognosis in OC, suggesting a better immunotherapy response. OC patients with low CRS score had a lower half maximal inhibitory concentration value of some drugs (Gemcitabine, Tamoxifen, and Nilotinib, etc) and lower score of some cancer-related hallmarks (Notch signaling, hypoxia, and glycolysis, etc). The current study developed an optimal CRS in OC, which acted as an indicator for the prognosis, stratifying risk and guiding treatment for OC patients.

An LRPPRC-HAPSTR1-PSMD14 interaction regulates tumor progression in ovarian cancer.

Ovarian cancer is the second most common cause of gynecologic cancer death. Chemoresistance and metastasis remain major challenges for current treatment. Previously, HAPSTR1 was shown to be a target gene of a paclitaxel resistance-associated miRNA. However, the biological function and underlying molecular mechanisms of HAPSTR1 in ovarian cancer progression remain unclear. Herein, we aimed to measure HAPSTR1 expression in ovarian cancer specimens and examine its correlations with clinical features and key functional interactions with other genes and proteins. An immunohistochemistry assay showed that HAPSTR1 was overexpressed in ovarian cancer tissues and was significantly associated with the FIGO stage and clinical outcome. HAPSTR1 overexpression promoted proliferation, invasion and migration in cellular and mouse models, whereas inhibition induced the opposite effects. In addition, HAPSTR1 stimulated the EMT pathway and affected the expression of autophagy biomarkers. Mechanistically, we demonstrated that HAPSTR1 is bound to LRPPRC and PSMD14 via immunoprecipitation. HAPSTR1 suppressed LRPPRC ubiquitination and recruited PSMD14 to interact with LRPPRC. Moreover, LRPPRC knockdown reversed HAPSTR1-mediated improvement in cellular proliferation, invasion, and migration. Our study is the first detailed and comprehensive analysis of HAPSTR1 in cancer progression and offers an experimental basis for the clinical treatment of ovarian carcinoma.

Inactivation of VRK1 sensitizes ovarian cancer to PARP inhibition through regulating DNA-PK stability

Ovarian cancer is the leading cause of gynecologic cancer death. Among the most innovative anti-cancer approaches, the genetic concept of synthetic lethality is that mutations in multiple genes work synergistically to effect cell death. Previous studies found that although vaccinia-related kinase-1 (VRK1) associates with DNA damage repair proteins, its underlying mechanisms remain unclear. Here, we found high VRK1 expression in ovarian tumors, and that VRK1 depletion can significantly promote apoptosis and cell cycle arrest. The effect of VRK1 knockdown on apoptosis was manifested by increased DNA damage, genomic instability, and apoptosis, and also blocked non-homologous end joining (NHEJ) by destabilizing DNA-PK. Further, we verified that VRK1 depletion enhanced sensitivity to a PARP inhibitor (PARPi), olaparib, promoting apoptosis through DNA damage, especially in ovarian cancer cell lines with high VRK1 expression. Proteins implicated in DNA damage responses are suitable targets for the development of new anti-cancer therapeutic strategies, and their combination could represent an alternative form of synthetic lethality. Therefore, normal protective DNA damage responses are impaired by combining olaparib with elimination of VRK1 and could be used to reduce drug dose and its associated toxicity. In summary, VRK1 represents both a potential biomarker for PARPi sensitivity, and a new DDR-associated therapeutic target, in ovarian cancer.

Anti-cancer effects of alpha lipoic acid, cisplatin and paclitaxel combination in the OVCAR-3 ovarian adenocarcinoma cell line.

Ovarian cancer is the leading cause of gynecological cancer deaths. One of the major challenges in treating ovarian cancer with chemotherapy is managing the resistance developed by cancer cells to drugs, while also minimizing the side effects caused by these agents In the present study, we aimed to examine the effects of a combination of alpha lipoic acid (ALA), with cisplatin and paclitaxel in ovarian cancer(OVCAR-3). The cytotoxic effects of ALA, cisplatin and paclitaxel on OVCAR-3 cells were determined. Four groups were formed: Control, ALA, Cisplatin + Paclitaxel, ALA + Cisplatin + Paclitaxel. The effects of single and combined therapy on cell migration, invasion and colony formation were analyzed. Changes in the expression of genes related to apoptosis, cell adhesion and cell cycle were analyzed with Real-time polymerase chain reaction(RT-PCR). The oxidative stress index and The Annexin V test were performed. The reduction in rapamycin-insensitive companion of mTOR(RICTOR) expression in the ALA + Cisplatin + Paclitaxel group was found statistically significant(p < 0.05). The decrease in MMP-9 and - 11 expressions the ALA + Cisplatin + Paclitaxel group was statistically significant(p < 0.05). The lowest values for mitogen-activated protein kinase(MAPK) proteins were found in the ALA + Cisplatin + Paclitaxel group. No colony formation was observed in the Cisplatin + Paclitaxel and ALA + Cisplatin + Paclitaxel groups. The lowest wound healing at 24h was seen in the ALA + Cisplatin + Paclitaxel group. This study is the first one to investigate the combined treatment of ALA, Cisplatin, Paclitaxel on OVCAR-3. While ALA alone was not effective, combined therapy with ALA, has been found to reduce cell invasion, especially wound healing in the first 24h, along with tumor cell adhesion.

Abstract B090: Gut microbial suppression of epithelial ovarian cancer and attenuation of chemoresistance: opportunity for probiotics in patient care to improve survival

Abstract Up to 80% of ovarian cancer patient tumors will recur, become platinum resistant, and require additional treatment. Platinum resistance is correlated with poor overall survival and reduced therapeutic options for epithelial ovarian cancer (EOC) patients, a leading cause of gynecologic cancer death. Our findings identify a microbial tumor suppressive activity that is disrupted by antibiotics including vancomycin, metronidazole, neomycin, and ampicillin. Starting with a retrospective clinical analysis of OC patients, we found antibiotic use during chemotherapy treatment is associated with poor overall survival. In pre-clinical studies, we found that broad spectrum antibiotics (ABX) therapy, including metronidazole, ampicillin, vancomycin, and neomycin, augments tumor growth of EOC and leads to resistance to cisplatin. In follow up studies we determined vancomycin and metronidazole are sufficient to accelerate ovarian cancer growth and response to cisplatin therapy. Mechanistically, we determined that tumors from ABX treated mice exhibited increased proliferation, reduced apoptosis, decreased DNA damage in cisplatin treated specimens, and increased angiogenesis compared to control treated mice. As these are functional indicators of increased cancer stem cells (CSCs), we analyzed the tumors by RNAseq and single cell spheroid analysis for stem cell frequency. Tumors from ABX treated immune competent mice contained a higher frequency of cisplatin-induced CSCs than tumors from control treated mice. Tumors from untreated mice did not show increased CSCs. We determined that ABX treatment unmasked a microbiome dependent immune suppressor of cancer stem cells as tumors from immune deficient mice exhibited cisplatin induced CSCs in presence or absence of ABX. Finally, we determined that repletion of the microbiome via cecal transplants derived from ABX or control treated mice to recolonize the microbiome of ABX treated mice is sufficient to ameliorate the chemoresistance and survival of ABX treated mice indicative of a gut-derived tumor suppressor. We identified microbial metabolites suppressed in ovarian cancer patients and reduced by ABX in mice as candidate compounds that underlie the tumor suppressive activity. Collectively, the findings indicate the gut microbiome delivers a tumor suppressive signal that is unmasked by ABX treatment. We propose a probiotic strategy as a complement to standard of care may yield improved outcomes in ovarian cancer treatment. Citation Format: Ofer Reizes, Laura Chambers, Chad M. Michener, Mark Brown, Justin D. Lathia, Mohammed Dwidar, Naseer Sangwan, Roberto Vargas, Zeneng Wang, Adeline Hajjar. Gut microbial suppression of epithelial ovarian cancer and attenuation of chemoresistance: opportunity for probiotics in patient care to improve survival [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B090.

Abstract A110: Targeting methionine metabolism inhibits ovarian cancer stem cells

Abstract Ovarian cancer (OC) is the leading cause of gynecologic cancer death. Platinum (Pt)- based chemotherapy can reprogram cancer cells to ovarian cancer stem cells (OCSCs) and contribute to disease recurrence. In the current study, we demonstrated that platinum drugs can enrich for OCSCs. In high grade serous ovarian cancer (HGSOC) cell lines, cisplatin treatment (IC50 for 16hrs) increased the percentage of cells with high aldehyde dehydrogenase (ALDH+) activity, a known OCSCs marker, and altered methionine (Met) metabolism. Extracellular Met uptake is converted to S-adenosyl-methionine (SAM) by methionine adenosyltransferase 2A (MAT2A), the rate-limiting enzyme of Met utilization. Short-term cisplatin treatment decreased SAM level and increased expression of MAT2A. It has been reported that CSCs have a high-flux metabolic state and are dependent on Met metabolism. We observed higher MAT2A expression in ALDH+ cells compared to the whole cell population, and Met depletion blocked the cisplatin-induced increase in %ALDH+ cells and spheroid formation ability. Furthermore, both MAT2A siRNA knockdown and the MAT2A inhibitor FIDAS-5 prevented cisplatin-induced increase in %ALDH+ cells, suggesting that blocking Met metabolism phenotypically inhibited the platinum enrichment of OCSCs. MAT2A inhibition also downregulated Cyclin E and arrested HGSOC cells in G1/S phase, indicating that a lower level of Met utilization re-established G1/S checkpoint in p53-mutant OC. As SAM is the universal methyl-group donor, it was of interest to examine whether the observed cisplatin-induced alterations in SAM level resulted in changes in DNA methylation. Methylation specific-PCR analysis demonstrated that siMAT2A or FIDAS-5 treatment of HGSOC cells inhibited cisplatin-induced hypermethylation of CpG islands of BRCA1 and ALDH1L1, a folate metabolic enzyme of which promoter hypermethylation is associated to tumor progression. Collectively, these results demonstrated a crucial role of Met metabolism in cisplatin-induced OCSCs enrichment. MAT2A has been recognized as a therapeutic target for the treatment of solid tumors and Met inhibition by targeting MAT2A could represent a therapeutic approach for inhibiting CSC in ovarian cancer. Citation Format: Shu Zhang, Tara X. Metcalfe, Christiane A. Hassel, Heather M. O'Hagan, Kenneth P. Nephew. Targeting methionine metabolism inhibits ovarian cancer stem cells [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A110.

Human papillomavirus serotypes and determinants among women with invasive cervical cancer in Katsina state, Northwest-Nigeria: a multicentre study.

Cervical cancer is the leading cause of gynaecological cancer death among women in developing countries and the most preventable of all gynaecological cancers as its infectious aetiological agent, human papillomavirus (HPV), is known. The knowledge of HPV serotype distribution in a sub-region is key to the implementation of an appropriate HPV vaccination programme. To assess the prevalence of HPV-DNA, serotypes and risk-determinants among women with invasive cervical cancer (ICC) in Katsina State, Northwestern Nigeria. This was a cross-sectional, multicenter study involving Federal Teaching Hospital Katsina, General Hospital Katsina and Turai Yar'adua Maternal and Child Hospital Katsina, Nigeria. Sixty-three women with histologically confirmed cervical cancer who fulfilled the criteria were recruited into the study. Tissue blocks with a confirmed diagnosis of ICC were taken to DNA Labs Kaduna for HPV-deoxyribonucleotide acid detection and typing. An interviewer-administered questionnaire developed for the study was used to obtain socio-demographic, reproductive characteristics and the other risk factors for HPV acquisition and persistence. The HPV-positivity rate in ICC was 95.5% while the prevalence of high-risk HPV (Hr-HPV)-DNA in the specimen was 54.6% with 13 HPV-serotypes detected, 9 Hr-HPV types (16,18,31,33,35,45,51,56,82) and 4 low-risk HPV types (6,44,81,89). The most commonly detected HPV serotype among women with a single HPV infection was HPV 81 (40.9%) followed by HPV 16 (28.8%). However, HPV 16 was the most common serotype among those with multiple HPV infections. Prevalence of other detected serotypes were HPV 31 (24.2%), 33 (24.2%), HPV 18 (10.6%), HPV 35 (3.0%), HPV 45 (9.1%), HPV 44 (1.5%), HPV 51 (3.0%), HPV 56 (3.0%), HPV 82 (1.5%), HPV 89 (1.5%) and HPV 6 (1.5%). Forty-four out of 63 women (69.8%) had a single HPV infection, 19 (30.2%) had multiple HPV infections and 15 (24.3%) were co-infected with HPV 16/31/33. There was a statistically significant association between HPV 16 and squamous cell carcinoma (SCC). The study demonstrates a prevalence of HPV-DNA as 95.5% among women with ICC. The most commonly detected HPV serotype was HPV 81 seen in 41% which was an uncommon finding. Furthermore, statistically significant associations between HPV serotypes 16 and 82 with SCC were detected.

The microbiome and ovarian cancer: insights, implications, and therapeutic opportunities

Ovarian cancer is the leading cause of gynecologic cancer death in the United States. Most ovarian cancer patients are diagnosed with advanced-stage disease, which poses a challenge for early detection and effective treatment. At present, cytoreductive surgery and platinum-based chemotherapy are foundational for patients with newly diagnosed ovarian cancer, but unfortunately, most patients will recur and die of their disease. Therefore, there is a significant need to seek innovative, novel approaches for early detection and to overcome chemoresistance for ovarian cancer patients. The microbiome, comprising diverse microbial communities inhabiting various body sites, is vital in maintaining human health. Changes to the diversity and composition of the microbial communities impact the microbiota-host relationship and are linked to diseases, including cancer. The microbiome contributes to carcinogenesis through various mechanisms, including altered host immune response, modulation of DNA repair, upregulation of pro-inflammatory pathways, altered gene expression, and dysregulated estrogen metabolism. Translational and clinical studies have demonstrated that specific microbes contribute to ovarian cancer development and impact chemotherapy’s efficacy. The microbiome is malleable and can be altered through different approaches, including diet, exercise, medications, and fecal microbiota transplantation. This review provides an overview of the current literature regarding ovarian cancer and the microbiome of female reproductive and gastrointestinal tracts, focusing on mechanisms of carcinogenesis and options for modulating the microbiota for cancer prevention and treatment. Advancing our understanding of the complex relationship between the microbiome and ovarian cancer may provide a novel approach for prevention and therapeutic modulation in the future.

Solitary lymph-nodal para-aortic recurrence in a patient with High Grade Serous Ovarian Cancer

Ovarian cancer is the second most common cause of gynecologic cancer death. The most common histologic category of epithelial ovarian cancer is High Grade Serous Ovarian Cancer (HGSOC). The initial management usually involves appropriate staging and debulking surgery. Otherwise, patients with unresectable disease receive neoadjuvant chemotherapy, and then undergo Interval Debulking Surgery (IDS). However, even cases with complete clinical response often experience a recurrence. While the primary debulking surgery is the standard of treatment, the role of secondary debulking surgery for recurrent ovarian cancer is still debatable. The most common sites of recurrences are pelvis and abdomen, whereas recurrence confined solely to lymph node is a rare event. Secondary cytoreductive surgery (SCS) for recurrent ovarian cancer presenting as isolated lymph node metastases has been associated with favorable long-term survival, although the resection of aortic metastatic lymph nodes could be related to severe intraoperative complications. In this article, we report a case of a 72-year-old patient with an isolated lymph-nodal para-aortic recurrence with a history of primary debulking surgery for high grade serous ovarian cancer FIGO stage IV, four years before, followed by received adjuvant chemotherapy, and maintenance therapy. The patient presented with a lymph node relapse down the ileocolic artery and submitted to radical resection of the metastatic lymph nodes.

Association of Clinical Trial Participation With Improved Overall Survival for Recurrent, Platinum-Resistant Ovarian Cancer

(Abstracted from Obstet Gynecol 2023;1(00):00) Despite recent advancements in treatment, ovarian cancer remains the leading cause of gynecologic cancer death in the United States. Advanced ovarian cancer is treated using surgery and platinum-based chemotherapy but ultimately recurs in most patients and becomes resistant to platinum chemotherapy.

Machine Learning Developed a Programmed Cell Death Signature for Predicting Prognosis, Ecosystem, and Drug Sensitivity in Ovarian Cancer.

Ovarian cancer (OC) is the leading cause of gynecological cancer death and the fifth most common cause of cancer-related death in women in America. Programmed cell death played a vital role in tumor progression and immunotherapy response in cancer. The prognostic cell death signature (CDS) was constructed with an integrative machine learning procedure, including 10 methods, using TCGA, GSE14764, GSE26193, GSE26712, GSE63885, and GSE140082 datasets. Several methods and single-cell analysis were used to explore the correlation between CDS and the ecosystem and therapy response of OC patients. The prognostic CDS constructed by the combination of StepCox (n = both) + Enet (alpha = 0.2) acted as an independent risk factor for the overall survival (OS) of OC patients and showed stable and powerful performance in predicting the OS rate of OC patients. Compared with tumor grade, clinical stage, and many developed signatures, the CDS had a higher C-index. OC patients with low CDS score had a higher level of CD8+ cytotoxic T, B cell, and M1-like macrophage, representing a related immunoactivated ecosystem. A low CDS score indicated a higher PD1 and CTLA4 immunophenoscore, higher tumor mutation burden score, lower tumor immune dysfunction and exclusion score, and lower tumor escape score in OC, demonstrating a better immunotherapy response. OC patients with high CDS score had a higher gene set score of cancer-related hallmarks, including angiogenesis, epithelial-mesenchymal transition, hypoxia, glycolysis, and notch signaling. The current study constructed a novel CDS for OC, which could serve as an indicator for predicting the prognosis, ecosystem, and immunotherapy benefits of OC patients.

Nomogram incorporating log odds of positive lymph nodes improves prognostic prediction for ovarian serous carcinoma: a real-world retrospective cohort study

ObjectivesOvarian serous carcinoma (OSC) is a major cause of gynaecological cancer death, yet there is a lack of reliable prognostic models. To address this, we developed and validated a nomogram...

Treatment of Ovarian Cancer Beyond PARP Inhibition: Current and Future Options.

Ovarian cancer is the leading cause of gynecological cancer death. Improved understanding of the biologic pathways and introduction of poly (ADP-ribose) polymerase inhibitors (PARPi) during the last decade have changed the treatment landscape. This has improved outcomes, but unfortunately half the women with ovarian cancer still succumb to the disease within 5years of diagnosis. Pathways of resistance to PARPi and chemotherapy have been studied extensively, but there is an unmet need to overcome treatment failure and improve outcome. Major mechanisms of PARPi resistance include restoration of homologous recombination repair activity, alteration of PARP function, stabilization of the replication fork, drug efflux, and activation of alternate pathways. These resistant mechanisms can be targeted to sensitize the resistant ovarian cancer cells either by rechallenging with PARPi, overcoming resistance mechanism or bypassing resistance pathways. Augmenting the PARPi activity by combining it with other targets in the DNA damage response pathway, antiangiogenic agents and immune checkpoint inhibitors can potentially overcome the resistance mechanisms. Methods to bypass resistance include targeting non-cross-resistant pathways acting independent of homologous recombination repair(HRR), modulating tumour microenvironment, and enhancing drug delivery systems such as antibody drug conjugates. In this review, we will discuss the first-line management of ovarian cancer, resistance mechanisms and potential strategies to overcome these.

Association of Preoperative Neutrophil to Lymphocyte Ratio in Patients with Epithelial Ovarian Tumor

Objective: Ovarian cancer is a leading cause of gynecological cancer death among women worldwide. Silent growth of the tumor and challenges associated with preoperative evaluation of an ovarian mass are responsible for late presentation. The aim of this study was to evaluate the association between preoperative neutrophil to lymphocyte ratio (NLR) and epithelial ovarian tumor. Methods: A total of 60 patients diagnosed with ovarian tumor who fulfilled the selection criteria were recruited as study population. The ovarian tumor was subsequently diagnosed by histopathological analysis as either malignant epithelial ovarian tumor or benign epithelial ovarian tumor. Preoperative demographic and laboratory variables are reviewed in all patients. Association of preoperative NLR was assessed in benign and malignant epithelial ovarian tumor using unpaired t test. Receiver operating characteristics curve was used to calculate optimal cut off value for NLR to predict ovarian cancer preoperatively. A p-value of &lt;0.05 was considered to indicate statistically significant differences. Results: There was statistically significant difference between the groups in terms of age, menopausal status, and NLR (all p=0.001, except for menopausal status p=0.007). NLR value was significantly higher (3.47±1.52) in patients with malignant ovarian tumor (p=0.001) than that of benign ovarian tumor. Higher NLR value predicted ovarian cancer at the cut-off value of 2.78, with 75.6% sensitivity and 78.9% specificity (95% CI, 0.97-1.0). Conclusion: Malignant epithelial ovarian tumor is associated with higher NLR. Preoperative NLR may be helpful for prediction of malignant ovarian tumor.

AhRR and PPP1R3C: Potential Prognostic Biomarkers for Serous Ovarian Cancer.

The lack of effective screening and successful treatment contributes to high ovarian cancer mortality, making it the second most common cause of gynecologic cancer death. Development of chemoresistance in up to 75% of patients is the cause of a poor treatment response and reduced survival. Therefore, identifying potential and effective biomarkers for its diagnosis and prognosis is a strong critical need. Copy number alterations are frequent in cancer, and relevant for molecular tumor stratification and patients' prognoses. In this study, array-CGH analysis was performed in three cell lines and derived cancer stem cells (CSCs) to identify genes potentially predictive for ovarian cancer patients' prognoses. Bioinformatic analyses of genes involved in copy number gains revealed that AhRR and PPP1R3C expression negatively correlated with ovarian cancer patients' overall and progression-free survival. These results, together with a significant association between AhRR and PPP1R3C expression and ovarian cancer stemness markers, suggested their potential role in CSCs. Furthermore, AhRR and PPP1R3C's increased expression was maintained in some CSC subpopulations, reinforcing their potential role in ovarian cancer. In conclusion, we reported for the first time, to the best of our knowledge, a prognostic role of AhRR and PPP1R3C expression in serous ovarian cancer.

FOXN3 inhibits the progression of ovarian cancer through negatively regulating the expression of RPS15A.

Ovarian cancer is the second most common cause of gynecological cancer death and has a high recurrence rate. FOXN3, a transcription inhibitor belonging to FOX family, has anti-tumor effects on several cancers. Bioinformatics analysis revealed that the expression of FOXN3 was downregulated in ovarian cancer specimens. However, the role of FOXN3 in ovarian cancer remains unclear. Herein, we investigated the role of FOXN3 in ovarian cancer using OVCAR3 and A2780 cells. Flow cytometry and CCK-8 analysis showed that overexpression of FOXN3 inhibited the proliferation and cell cycle progression of OVCAR3 cells. Cell invasion and migration abilities were decreased by FOXN3 according to transwell and wound healing assays. The suppression of FOXN3 on angiogenesis in OVCAR3 cells was evidenced by reduced vessel formation and VEGFA protein expression. Taken together, FOXN3 had an inhibitory effect on the proliferation, migration, invasion and angiogenesis of OVCAR3 cells, while its knockdown exhibited an opposite effect in A2780 cells. By inoculation of FOXN3-overexpressing cells into nude mice, tumorigenesis assay demonstrated that FOXN3 could delay the growth of ovarian cancer cells in vivo. The interaction between FOXN3 and RPS15A was preliminarily explored via dual-luciferases assay and ChIP. FOXN3 was confirmed to bind to the promoter (at - 1588/- 1581 and - 1476/- 1467) of gene RPS15A and inhibit its transcriptional expression. We further found that overexpression of RPS15A diminished the inhibition of FOXN3 on ovarian cancer cell malignant behaviors. These findings indicate that FOXN3 negatively regulates the expression of RPS15A and thus suppresses the progression of ovarian cancer.

Therapeutic implications of the tumor microenvironment in ovarian cancer patients receiving PD-1/PD-L1 therapy.

Epithelial ovarian cancer (EOC) ranks as the second most common cause of gynecologic cancer death. The conventional treatment for patients with EOC is postoperative therapy along with platinum chemotherapy. However, a more efficient treatment regimen is of great need for these patients diagnosed with advanced disease (FIGO stages III-IV), whose survival is approximately 29%. Immunotherapy seems to be an encouraging therapeutic strategy for EOC. Given the crucial role in the complicated interactions between tumor cells and other cells, the tumor microenvironment (TME) influences the response to immunotherapy. In this review, we discuss feasible strategies for EOC immunotherapy by exploiting the reciprocity of cancer cells and the constituents of the TME.