High-grade Ovarian Cancer Research Articles

Decoding β-catenin expression patterns in ovarian serous carcinoma with clinicopathological implications: insights from National Cancer Institute.

This study aimed to examine the immunohistochemical expression of β-catenin in serous ovarian carcinoma and to investigate its relationship with clinicopathological features and disease outcomes. A retrospective analysis was conducted on 67 cases of serous ovarian carcinoma diagnosed at the Pathology Department of the Egyptian National Cancer Institute, Cairo University, between January 1, 2015, and December 31, 2017. The age of the patients ranged from 26 to 76years. Aberrant β-catenin expression was defined by the presence of cytoplasmic staining with or without membranous staining in at least 10% of tumor cells. Of the cases analyzed, thirty exhibited cytoplasmic staining, 18 demonstrated preserved expression on the cell membrane, 15 showed combined cytoplasmic and membranous staining, while four cases were entirely negative. Significant correlations were observed between β-catenin positivity and both tumor grade and p53 expression, with p values of 0.004 for each correlation. Positive β-catenin expression significantly correlated with tumor grade in serous ovarian carcinoma. Most low-grade serous carcinoma cases exhibited membranous β-catenin expression, whereas high-grade serous carcinoma cases predominantly displayed cytoplasmic staining. Therapeutic strategies aimed at inhibiting β-catenin signaling could provide a novel approach to improving outcomes for patients with high-grade ovarian cancer.

Hyperthermic intraperitoneal chemotherapy for recurrent ovarian cancer (CHIPOR): a randomised, open-label, phase 3 trial.

Hyperthermic intraperitoneal chemotherapy (HIPEC) at interval cytoreductive surgery for ovarian cancer improves overall survival but its role in recurrent disease is uncertain. We aimed to compare outcomes in patients treated with or without HIPEC during surgery for recurrent ovarian cancer. The multicentre, open-label, randomised, phase 3 CHIPOR trial was conducted at 31 sites in France, Belgium, Spain, and Canada, and enrolled patients with first relapse of epithelial ovarian cancer at least 6 months after completing platinum-based chemotherapy. Eligible patients were aged 18 years or older with WHO performance status of less than 2. After six cycles of platinum-based chemotherapy (and optional bevacizumab), patients amenable to complete cytoreductive surgery were randomly assigned centrally in a 1:1 ratio, using a web-based system and a minimisation procedure, during surgery to receive HIPEC (cisplatin 75 mg/m2 in 2 L/m2 of serum at 41±1°C for 60 min) or not, stratified by centre, completeness of cytoreduction score, platinum-free interval, and latterly, planned poly(ADP-ribose) polymerase inhibitor use. The primary endpoint was overall survival, analysed on an intention-to-treat basis in all randomly assigned patients. This ongoing trial is registered with ClinicalTrials.gov, NCT01376752. Between May 11, 2011, and May 14, 2021, 415 female patients were randomly assigned (207 HIPEC, 208 no HIPEC). At the primary analysis (median follow-up 6·2 years, IQR 4·1-8·1), 268 (65%) patients had died (126 [61%] of 207 in the HIPEC group; 142 [68%] of 208 in the no-HIPEC group). Overall survival was significantly improved with HIPEC (stratified hazard ratio 0·73, 95% CI 0·56-0·96; p=0·024). Median overall survival was 54·3 months (95% CI 41·9-61·7) with HIPEC versus 45·8 months (38·9-54·2) without. Grade 3 or worse adverse events within 60 days after surgery occurred in 102 (49%) of 207 patients receiving HIPEC versus 56 (27%) of 208 receiving no HIPEC, the most common being anaemia (47 [23%] vs 30 [14%]), hepatotoxicity (23 [11%] vs 18 [9%]), electrolyte disturbance (28 [14%] vs two [1%]), and renal failure (20 [10%] vs three [1%]). There were three deaths within 60 days of surgery, all in the no-HIPEC group. Adding HIPEC to cytoreductive surgery after response to platinum-based chemotherapy at first epithelial ovarian cancer recurrence significantly improved overall survival. When treating patients with late first relapse of high-grade serous or high-grade endometrioid ovarian cancer amenable to complete cytoreductive surgery at specialist centres, platinum-based HIPEC should be considered to extend overall survival. French National Cancer Institute and French League Against Cancer.

The Efficacy and Safety of Folate Receptor α-Targeted Antibody-Drug Conjugate Therapy in Patients With High-Grade Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancers: A Systematic Review and Meta-Analysis.

Antibody-drug conjugates (ADC) have emerged as a highly promising systemic option in the treatment of recurrent ovarian cancer. The present study aimed to evaluate the treatment efficacy of folate receptor α (FRα)-targeting ADCs, associated treatment-related adverse events (TRAEs), and their impact on treatment safety. We conducted an electronic search to identify prospective trials of single-agent ADCs targeting FRα and those combined with chemotherapy in recurrent ovarian cancer. Information regarding the objective response rate (ORR) and TRAEs was collectively analyzed, and differences in subgroups based on FRα receptor expression levels were investigated. The protocol was registered with PROSPERO (CRD42023491151). Ten studies with a total of 940 patients (859 treated with Mirvetuximab soravtansine-gynx (MIRV)), 45 with Farletuzumab Ecteribulin (MORAb-202), and 36 with Luveltamab Tazevibulin (STRO-002) were included in this meta-analysis. Based on the pooled data, the ORR of the entire cohort was 37% (95% CI: 0.30-0.43), while that of the high-FRα expression group was 34% (95% CI: 0.26-0.42). The incidence of grade ≥ 3 adverse events was 27% (95% CI: 0.19-0.36). FRα-targeting ADCs, including MIRV, demonstrated definite efficacy and good safety as novel choices for second-line and beyond treatment of advanced or recurrent ovarian cancer. Patients with high FRα expression showed ORR and PFS benefits similar to those in the overall cohort.

Sleep characteristics and recurrence in platinum-sensitive ovarian cancer survivors: A prospective cohort study

ObjectiveTo describe characteristics of sleep (quality, duration, efficiency, and insomnia) in a cohort of high-grade epithelial ovarian cancer (EOC) survivors who have completed and responded to first-line chemotherapy, and to explore their relationships with disease recurrence. MethodsIn this cohort of 97 women, sleep and other factors were assessed at baseline and 4 months later. The distribution of participants by categories of sleep characteristics were calculated. Hazard ratios (HRs) and 95 % confidence intervals (95 % CI) for the association between each sleep characteristic and recurrence were estimated using the Cox proportional hazards model, and adjusted for confounding using propensity scores. Associations were estimated for all women and among those defined as fully platinum-sensitive. ResultsAt baseline, just over half of participants (52.6 % to 56.7 %) had poor sleep quality, efficiency and duration, while most (62.9 %) did not experience insomnia. Distributions remained similar 4 months later. During follow-up, 47 recurrences occurred. Among all participants, HRs (95 % CIs) of recurrence were close to the value of 1, indicating no association, for sleep quality and efficiency, 1.22 (0.66–2.23) for not meeting vs. meeting sleep duration guidelines and 0.68 (0.34–1.39) for the presence vs. absence of insomnia. In fully platinum-sensitive women, the HRs (95 % CIs) were 1.50 (0.64–3.53) for not meeting duration guidelines, 1.25 (0.56–2.79) for poor sleep efficiency, 1.44 (0.55–3.72) for the presence of insomnia, and remained null for sleep quality. ConclusionMost EOC survivors have poor sleep quality, duration, and efficiency. Research with larger sample sizes is required to better understand the relationship between these sleep characteristics and the risk of recurrence.

Determination of platinum-resistance of women with ovarian cancer by FTIR spectroscopy combined with multivariate analyses and machine learning methods

Patients with high-grade ovarian cancer have a poor prognosis, thus effective treatment remains an unmet medical issue of high importance. Moreover, finding the reason for resistance to cisplatin is a crucial task for the improvement of anti-cancer drugs. In this study, we showed for the first time a chemical difference in a serum collected from platinum-resistance and platinum-sensitive women suffering from ovarian cancer using Fourier Transform InfraRed (FTIR) spectroscopy followed by a data analysis by Principal Component Analysis (PCA), Hierarchical Component Analysis (HCA) and 4 different machine learning algorithms. Obtained results showed a shift of PO2-symmetric vibrations, amide III and amide II were observed on the FTIR spectrum of the serum collected from platinum-resistance women in comparison with the spectrum of the serum from platinum-sensitive women. Furthermore, PCA analysis clearly demonstrated the most important role of amide II and amide I in the differentiation of platinum-sensitive and platinum-resistance women. In addition, machine learning algorithms showed the important role of wavenumber at 1631 cm-1(amide I) and wavenumber at 2993 cm-1 (asymmetric stretching CH3 vibrations). The accuracy of the obtained results was above 92%. Summarizing, FTIR can be used in detection platinum-resistance phenomena.

The Diversity of Methylation Patterns in Serous Borderline Ovarian Tumors and Serous Ovarian Carcinomas.

Background: Changes in DNA methylation patterns are a pivotal mechanism of carcinogenesis. In some tumors, aberrant methylation precedes genetic changes, while gene expression may be more frequently modified due to methylation alterations than by mutations. Methods: Herein, 128 serous ovarian tumors were analyzed, including borderline ovarian tumors (BOTS) with (BOT.V600E) and without (BOT) the BRAF V600E mutation, low-grade (lg), and high-grade (hg) ovarian cancers (OvCa). The methylome of the samples was profiled with Infinium MethylationEPIC microarrays. Results: The biggest number of differentially methylated (DM) CpGs and regions (DMRs) was found between lgOvCa and hgOvCa. By contrast, the BOT.V600E tumors had the lowest number of DM CpGs and DMRs compared to all other groups and, in relation to BOT, their genome was strongly downmethylated. Remarkably, the ten most significant DMRs, discriminating BOT from lgOvCa, encompassed the MHC region on chromosome 6. We also identified hundreds of DMRs, being of potential use as predictive biomarkers in BOTS and hgOvCa. DMRs with the best discriminative capabilities overlapped the following genes: BAIAP3, IL34, WNT10A, NEU1, SLC44A4, and HMOX1, TCN2, PES1, RP1-56J10.8, ABR, NCAM1, RP11-629G13.1, AC006372.4, NPTXR in BOTS and hgOvCa, respectively. Conclusions: The global genome-wide hypomethylation positively correlates with the increasing aggressiveness of ovarian tumors. We also assume that the immune system may play a pivotal role in the transition from BOTS to lgOvCa. Given that the BOT.V600E tumors had the lowest number of DM CpGs and DMRs compared to all other groups, when methylome is considered, such tumors might be placed in-between BOT and OvCa.

GOG-3097/ENGOT-ov81/GTG-UK/RAMP 301: a phase 3, randomized trial evaluating avutometinib plus defactinib compared with investigator’s choice of treatment in patients with recurrent low grade serous ovarian cancer

BackgroundThere are no approved treatments specifically for low grade serous ovarian cancer; current standard of care treatment options are limited in efficacy and tolerability. The combination of avutometinib with defactinib...

High-grade serous ovarian cancer development and anti-PD-1 resistance is driven by IRE1α activity in neutrophils

ABSTRACT High-grade serious ovarian cancer (HGSOC) is an aggressive malignancy that remains refractory to current immunotherapies. While advanced stage disease has been extensively studied, the cellular and molecular mechanisms that promote early immune escape in HGSOC remain largely unexplored. Here, we report that primary HGSO tumors program neutrophils to inhibit T cell anti-tumor function by activating the endoplasmic reticulum (ER) stress sensor IRE1α. We found that intratumoral neutrophils exhibited overactivation of ER stress response markers compared with their counterparts at non-tumor sites. Selective deletion of IRE1α in neutrophils delayed primary ovarian tumor growth and extended the survival of mice with HGSOC by enabling early T cell-mediated tumor control. Notably, loss of IRE1α in neutrophils sensitized tumor-bearing mice to PD-1 blockade, inducing HGSOC regression and long-term survival in ~ 50% of the treated hosts. Hence, neutrophil-intrinsic IRE1α facilitates early adaptive immune escape in HGSOC and targeting this ER stress sensor might be used to unleash endogenous and immunotherapy-elicited immunity that controls metastatic disease.

506LBA (PB-506) LBA Posters: Ablation of Src Family Kinases FGR in hosts reduces confers response of high-grade ovarian cancer to immune checkpoint blockade treatment

506LBA (PB-506) LBA Posters: Ablation of Src Family Kinases FGR in hosts reduces confers response of high-grade ovarian cancer to immune checkpoint blockade treatment

Vitamin D Significantly Inhibits Carcinogenesis in the Mogp-TAg Mouse Model of Fallopian Tube Ovarian Cancer.

Epidemiological and observational studies suggest that vitamin D has potential for the chemoprevention of ovarian cancer. The anticancer effect of vitamin D in the fallopian tube epithelium (FTE), which is now thought to harbor the precursor cells for high grade ovarian cancer, is not known. The purpose of this study was to investigate whether vitamin D can inhibit carcinogenesis in the mogp-TAg fallopian tube (FT) ovarian cancer mouse model and examine underlying mechanisms. To test this hypothesis, 3 groups of 40 5-week-old female mogp-TAg mice were divided equally into two cohorts of 20 mice, treated with either vehicle (vitamin D solvent) or the active 1,25(OH)2D3 analogue EB1089, delivered via mini-pump or IP injection or cholecalciferol delivered in the feed. The FTs were characterized histologically and pathologically after 3 and 7 weeks of treatment. The effect of vitamin D on cultured human FTE cells was also examined. After 3 weeks, vitamin D, delivered as either cholecalciferol or EB1089 significantly inhibited FT carcinogenesis. After 7 weeks, cholecalciferol significantly reduced p53 signatures, serous tubal epithelial carcinoma, FT cancer, and plasma CA125 while increasing apoptosis in the FTE. EB1089 had no significant effect on FT carcinogenesis at 7 weeks. Cholecalciferol significantly reduced proliferation and increased apoptosis in vitro in p53-altered FTE cells. In conclusion, vitamin D inhibited FT carcinogenesis by clearing cells with p53 alterations. These data suggest that vitamin D has merit for the chemoprevention of fallopian tube/ovarian cancer. The optimal chemopreventive effect may be dependent on the route of vitamin D administration.

Increased peritoneal TGF-β1 is associated with ascites-induced NK-cell dysfunction and reduced survival in high-grade epithelial ovarian cancer.

Natural killer (NK) cell therapy represents an attractive immunotherapy approach against recurrent epithelial ovarian cancer (EOC), as EOC is sensitive to NK cell-mediated cytotoxicity. However, NK cell antitumor activity is dampened by suppressive factors in EOC patient ascites. Here, we integrated functional assays, soluble factor analysis, high-dimensional flow cytometry cellular component data and clinical parameters of advanced EOC patients to study the mechanisms of ascites-induced inhibition of NK cells. Using a suppression assay, we found that ascites from EOC patients strongly inhibits peripheral blood-derived NK cells and CD34+ progenitor-derived NK cells, albeit the latter were more resistant. Interestingly, we found that higher ascites-induced NK cell inhibition correlated with reduced progression-free and overall survival in EOC patients. Furthermore, we identified transforming growth factor (TGF)-β1 to correlate with ascites-induced NK cell dysfunction and reduced patient survival. In functional assays, we showed that proliferation and anti-tumor reactivity of CD34+ progenitor-derived NK cells are significantly affected by TGF-β1 exposure. Moreover, inhibition of TGF-β1 signaling with galunisertib partly restored NK cell functionality in some donors. For the cellular components, we showed that the secretome is associated with a different composition of CD45+ cells between ascites of EOC and benign reference samples with higher proportions of macrophages in the EOC patient samples. Furthermore, we revealed that higher TGF-β1 levels are associated with the presence of M2-like macrophages, B cell populations and T-regulatory cells in EOC patient ascites. These findings reveal that targeting TGF-β1 signaling could increase NK cell immune responses in high-grade EOC patients.

Abstract C020: Nuclear encoded mitochondrial protein MAGMAS as a potential predictor of taxane sensitivity in advanced prostate cancer patients and differential diagnostic marker of tumor aggressiveness in men of African ancestry

Abstract Prostate cancer (PCa) is the most commonly diagnosed malignancy and the second leading cause of cancer-related death among men in the United States (U.S.). Strikingly, men of African ancestry (AA) are 1.7 times more likely to be diagnosed with PCa and more than twice as likely to die of PCa than men of European origin (EU). These disparities are driven by socioeconomic, lifestyle, environmental, and biological/genetic factors. Prostate-specific antigen screening is limited in identifying men with aggressive PCa and exposes men to increased harm with minimal reduction in mortality from PCa. Specifically, several studies report that men of AA are considered to have low-risk prostate cancer by clinical parameters, and those who enrolled in active surveillance programs progress to a higher Gleason-grade cancer and high-volume status than men of EA. Also, men of AA in low to moderate-risk groups appear to be at a higher risk for biochemical recurrence after curative-intent treatment. Therefore, there is a need to understand molecular mechanisms underlying PCa aggressiveness in men of AA that are translatable to the clinic as reliable biomarkers and for the development of novel therapeutic targets. Evidence supports that the mitochondria have a fundamental influence on all steps of oncogenesis, including malignant transformation, tumor progression, and treatment resistance. Regarding cancer health disparities, genes encoding mitochondrial complexes involved in oxidative phosphorylation are upregulated to a greater extent in tumor specimens from AA patients than those from EA patients, supporting the rationale for investigating the role of mitochondria in cancer health disparities. This study investigates Magmas, a nuclear-encoded mitochondrial protein, as a potential mitochondrial marker for PCa tumor aggressiveness and a therapeutic target for advanced PCa. Several observations support the rationale for this study: 1) Magmas overexpression in multiple aggressive cancer subtypes, including high-grade prostate, ovarian cancer, and malignant gliomas. 2) AA PCa cell line overexpresses Magmas similar to chemo-resistant PCa cells, whereas the EA cell line is shown to exhibit lower expression. 3) In human cells, overexpression of Magmas suppresses oxidative stress by regulating the reactive oxygen species (ROS) levels. 4) In chemo-resistant PCa cell lines, pharmacological inhibition of Magmas re-sensitized PCa cells to taxane treatment; and 5) non-cytotoxic pharmacological inhibition of Magmas in chemo-resistant PCa cells dramatically reduced clonogenicity potential. We will evaluate the hypothesis that AA PCa tissue will overexpress Magmas and that overexpression will predict tumor aggressiveness, and 2) that pharmacological inhibition of Magmas will overcome treatment resistance in advanced PCa models. The proposed exploratory study is highly relevant as it will reveal the biological basis for race-related differential expression of Magmas, providing critical insights into mitochondrial determinants that contribute to PCa mortality disparities. Citation Format: Alfonso Duran, Kristen Whitley, Krystal Santiago, Bhaskar Das, Carlos Casiano, Frankis Almaguel. Nuclear encoded mitochondrial protein MAGMAS as a potential predictor of taxane sensitivity in advanced prostate cancer patients and differential diagnostic marker of tumor aggressiveness in men of African ancestry [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C020.

Potential of AKNA as a Predictive Biomarker for Ovarian Cancer and Its Relationship to Tumor Grading.

Ovarian cancer exhibits a significant prevalence and incidence on a global scale. Low-grade or high-grade epithelial-type ovarian cancer can be classified by using the dualistic model. Inflammation has been associated with AKNA protein by cancer researchers. The potential of AKNA as a cancer biomarker is supported by its significance and association with ovarian carcinoma. Uninvestigated is this enormous potential. This study examines the correlation between AKNA expression in low-grade and high-grade ovarian tumors and its utility as a predictive biomarker for ovarian cancer. This study examined a total of thirty-one samples, which were classified into three groups: cyst, low-grade, and high-grade ovarian carcinoma. The departmental archive was accessed for the following information: age, tumor size, nuclear grade, mitosis, ovary volume, implant tumor status, lymph vascular invasion status, lymph node metastasis, and tumor-infiltrating lymphocyte. The expression of AKNA was determined using IHC staining. The information was collected and analyzed via analysis of variance. The AKNA H-score shows the mean difference between all three groups (P < 0.001). Cysts had the highest AKNA expression, followed by low-grade and high-grade ovarian carcinoma. Higher-grade ovarian cancer expressed less AKNA compared to cysts or low-grade forms of the disease. This considerable difference suggests that AKNA might predict ovarian cancer tumor grade.

749P Luveltamab tazevibulin, an antifolate receptor alpha (FRα) antibody-drug conjugate (ADC), in combination with bevacizumab (bev) in patients with recurrent high-grade epithelial ovarian cancer (EOC): STRO-002-GM2 phase I study

749P Luveltamab tazevibulin, an antifolate receptor alpha (FRα) antibody-drug conjugate (ADC), in combination with bevacizumab (bev) in patients with recurrent high-grade epithelial ovarian cancer (EOC): STRO-002-GM2 phase I study

757P Sustained long-term responders to niraparib maintenance in recurrent platinum-sensitive high-grade ovarian cancer (PSROC): A subanalysis of the GEICO-88R study

757P Sustained long-term responders to niraparib maintenance in recurrent platinum-sensitive high-grade ovarian cancer (PSROC): A subanalysis of the GEICO-88R study

Constraint-based modelling predicts metabolic signatures of low and high-grade serous ovarian cancer

Ovarian cancer is an aggressive, heterogeneous disease, burdened with late diagnosis and resistance to chemotherapy. Clinical features of ovarian cancer could be explained by investigating its metabolism, and how the regulation of specific pathways links to individual phenotypes. Ovarian cancer is of particular interest for metabolic research due to its heterogeneous nature, with five distinct subtypes having been identified, each of which may display a unique metabolic signature. To elucidate metabolic differences, constraint-based modelling (CBM) represents a powerful technology, inviting the integration of ‘omics’ data, such as transcriptomics. However, many CBM methods have not prioritised accurate growth rate predictions, and there are very few ovarian cancer genome-scale studies. Here, a novel method for CBM has been developed, employing the genome-scale model Human1 and flux balance analysis, enabling the integration of in vitro growth rates, transcriptomics data and media conditions to predict the metabolic behaviour of cells. Using low- and high-grade ovarian cancer, subtype-specific metabolic differences have been predicted, which have been supported by publicly available CRISPR-Cas9 data from the Cancer Cell Line Encyclopaedia and an extensive literature review. Metabolic drivers of aggressive, invasive phenotypes, as well as pathways responsible for increased chemoresistance in low-grade cell lines have been suggested. Experimental gene dependency data has been used to validate areas of the pentose phosphate pathway as essential for low-grade cellular growth, highlighting potential vulnerabilities for this ovarian cancer subtype.

Does an Autoimmune Disorder Following Ovarian Cancer Diagnosis Affect Prognosis?

We investigated whether developing an autoimmune disorder (AID) following a high-grade epithelial ovarian cancer diagnosis improves overall survival. This retrospective study included data from women treated for high-grade serous, endometrioid, or transitional cell ovarian, fallopian tube, or peritoneal cancer FIGO stage III or IV at a Swiss cantonal gynecological cancer center (2008-2023). We used Kaplan-Meier estimates and the Cox proportional hazards model using time-varying covariates for the survival function estimation. In all, 9 of 128 patients developed an AID following a cancer diagnosis. The median time from cancer diagnosis to AID was 2 years (IQR 2-5). These women survived for a median of 3031 days (IQR 1765-3963) versus 972 days (IQR 568-1819) for those who did not develop an AID (p = 0.001). The median overall survival of nine women with a pre-existing AID was 1093 days (IQR 716-1705), similar to those who never had an AID. The multivariate analyses showed older age (p = 0.003, HR 1.04, 95% CI 1.013-1.064) was associated with a poorer prognosis, and developing an AID after a cancer diagnosis was associated with longer survival (p = 0.033, HR 0.113, 95% CI 0.015-0.837). Clinical manifestations of autoimmune disorders following ovarian cancer diagnoses were associated with better overall survival (8 versus 2.7 years), indicating an overactive immune response may improve cancer control.

Synergistic antitumor effect of liposomal-based formulations of olaparib and topotecan in primary epithelial ovarian cancer cells

BackgroundOlaparib is a PARP inhibitor inducing synthetic lethality in tumors with deficient homologous recombination (HRD) caused by BRCA1/2 mutations. The FDA has approved monotherapy for first-line platinum-sensitive, recurrent high-grade epithelial ovarian cancer. Combination therapy alongside DNA-damaging therapeutics is a promising solution to overcome the limited efficacy in patients with HRD. The present study was designed to develop topotecan- and olaparib-loaded liposomes (TLL and OLL) and assess the effectiveness of their combination in patient-derived ovarian cancer samples.MethodsWe used HEOC, four clear-cell tumors (EOC 1–4), malignant ascites, and an OCI-E1p endometrioid primary ovarian cancer cell line and performed NGS analysis of BRCA1/2 mutation status. Antiproliferative activity was determined with the MTT assay. The Chou-Talalay algorithm was used to investigate the in vitro pharmacodynamic interactions of TLLs and OLLs.ResultsThe OLL showed significantly higher efficacy in all ovarian cancer types with wild-type BRCA1/2 than a conventional formulation, suggesting potential for increased in vivo efficacy. The TLL revealed substantially higher toxicity to EOC 1, EOC 3, ascites and lower toxicity to HEOC than the standard formulation, suggesting better therapeutic efficacy and safety profile. The combination of studied compounds showed a higher reduction in cell viability than drugs used individually, demonstrating a synergistic antitumor effect at most of the selected concentrations.ConclusionsThe concentration-dependent response of different ovarian cancer cell types to combination therapy confirms the need for in vitro optimization to maximize drug cytotoxicity. The OLL and TLL combination is a promising formulation for further animal studies, especially for eliminating epithelial ovarian cancer with wild-type BRCA1/2.

Pembrolizumab plus chemotherapy in frontline treatment of advanced ovarian cancer: Clinical and translational results from a phase 2 trial.

The efficacy and feasibility of pembrolizumab combined with chemotherapy in frontline management of advanced high-grade epithelial ovarian cancer (EOC) is unknown. Additionally, modification of the tumor microenvironment following neoadjuvant therapy is not well understood. In this single-arm phase 2 trial (this study was registered at ClinicalTrials.gov: NCT02520154), eligible patients received up to 4 cycles of neoadjuvant chemotherapy followed by interval cytoreduction, 3 cycles of adjuvant intravenous carboplatin/weekly paclitaxel/pembrolizumab, and finally maintenance pembrolizumab until progression or toxicity (maximum 20 cycles). The primary endpoint was progression-free survival (PFS). Secondary endpoints included feasibility, toxicity, and overall survival (OS). PD-L1 staining, multiplex immunofluorescence staining, RNA sequencing, reverse-phase protein array analyses were performed on pre- and post-chemotherapy samples. Thirty-one eligible patients were enrolled. Median PFS and OS was 14.88 (95% CI 12.39-23.00) and 57.43months (95% CI 30.88-not reached), respectively. Among those with PD-L1 combined positive score (CPS) ≥10, the median PFS and OS were not reached compared to those with CPS <10 (10.50 and 30.90months, respectively). Feasibility was met, with all patients completing their planned adjuvant cycles. Treatment discontinuation due to immune-related toxicity occurred in 6 patients (20%). Chemotherapy resulted in an infiltration of anti-tumor immune cells in the tumor microenvironment. Samples of patients with the best PFS demonstrated increased expression of NF-κB, TGF-β, and β-catenin signaling. Pembrolizumab with chemotherapy was feasible and resulted in PFS within the historical range for this EOC population. Patients with CPS ≥10 may benefit more from this regimen, and future studies should investigate this potential biomarker. This investigator-initiated trial was funded by Merck.

The Clinical Significance of CRNDE Gene Methylation, Polymorphisms, and CRNDEP Micropeptide Expression in Ovarian Tumors.

CRNDE is an oncogene expressed as a long non-coding RNA. However, our team previously reported that the CRNDE gene also encodes a micropeptide, CRNDEP. The amino acid sequence of CRNDEP has recently been revealed by other researchers, too. This study aimed to investigate genetic alterations within the CRNDEP-coding region of the CRNDE gene, methylation profiling of this gene, and CRNDEP expression analysis. All investigations were performed on clinical material from patients with ovarian tumors of diverse aggressiveness. We found that CRNDEP levels were significantly elevated in highly aggressive tumors compared to benign neoplasms. Consistently, a high level of this micropeptide was a negative, independent, prognostic, and predictive factor in high-grade ovarian cancer (hgOvCa) patients. The cancer-promoting role of CRNDE(P), shown in our recent study, was also supported by genetic and epigenetic results obtained herein, revealing no CRNDEP-disrupting mutations in any clinical sample. Moreover, in borderline ovarian tumors (BOTS), but not in ovarian cancers, the presence of a single nucleotide polymorphism in CRNDE, rs115515594, significantly increased the risk of recurrence. Consistently, in BOTS only, the same genetic variant was highly overrepresented compared to healthy individuals. We also discovered that hypomethylation of CRNDE is associated with increased aggressiveness of ovarian tumors. Accordingly, hypomethylation of this gene's promoter/first exon correlated with hgOvCa resistance to chemotherapy, but only in specimens with accumulation of the TP53 tumor suppressor protein. Taken together, these results contribute to a better understanding of the role of CRNDE(P) in tumorigenesis and potentially may lead to improvements in screening, diagnosis, and treatment of ovarian neoplasms.