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16 pages, 3149 KiB

Open AccessArticle

GW0742 as a Potential TRα and TRβ Antagonist Reduces the Viability and Metabolic Activity of an Adult Granulosa Tumour Cell Line and Simultaneously Upregulates TRβ Expression

by Justyna Gogola-Mruk, Izabela Kumor, Gabriela Wojtaszek, Karolina Kulig and Anna Ptak

Cancers 2024, 16(23), 4069; https://doi.org/10.3390/cancers16234069 - 5 Dec 2024

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Abstract

Background/Objectives: Clinical studies have demonstrated a correlation between alterations in the expression level of TRα and TRβ receptors in ovarian cancer cells and overall survival. Celecoxib and GW0742, commonly known as a COX-2 inhibitor and a PPARβ/δ agonist, are novel thyroid hormone receptor [...] Read more.

Background/Objectives: Clinical studies have demonstrated a correlation between alterations in the expression level of TRα and TRβ receptors in ovarian cancer cells and overall survival. Celecoxib and GW0742, commonly known as a COX-2 inhibitor and a PPARβ/δ agonist, are novel thyroid hormone receptor antagonists that bind to TRβ or both TRα and TRβ. Methods: The study was conducted on a non-luteinized ovarian granulosa cell line (HGrC1) and two rare ovarian cancer cell lines (COV434 and KGN). The expression of TRα and TRβ at the gene and protein levels was examined by real-time PCR and Western blot, respectively. The impact of GW0742 and celecoxib on the cell viability of the HGrC1, COV434 and KGN lines was evaluated using the PrestoBlue™ Cell Viability Reagent. The metabolic activity of the cells was analysed using the Seahorse XFp Analyzer. Results: Initially, we observed that the gene and protein expression levels of TRα and TRβ were higher in COV434 and KGN cells than in HGrC1 cells. Subsequently, it was demonstrated that T₃ enhances the viability of HGrC1, COV434 and KGN cells. Furthermore, autoregulatory feedback loops were not observed during TRα or TRβ signalling in ovarian cancer cells, in contrast to the findings in healthy granulosa cells. Finally, we demonstrated that GW0742 reduced the viability and metabolic activity of granulosa cell tumours (GCTs). Simultaneously, we observed that GW0742 upregulated the expression of TRβ in GCT. Conclusions: These findings suggest that GW0742 may be a novel adjuvant therapy for GCTs expressing TRα and TRβ. Full article

(This article belongs to the Special Issue Advances in Ovarian Cancer Research and Treatment)

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17 pages, 1972 KiB

Open AccessArticle

Dual Targeting of CX₃CR1 and PARP in Models of High-Grade Serous Ovarian Carcinoma

by Jia Xie and Maria V. Barbolina

Cancers 2024, 16(22), 3728; https://doi.org/10.3390/cancers16223728 - 5 Nov 2024

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Abstract

Background/Objectives: Clinical use of poly(ADP-ribose) polymerase inhibitors (PARPis) against metastatic high-grade serous ovarian carcinoma (HGSOC) is limited to cases with deficient a homologous recombination (HR). Our objective was to determine whether the impairment of the fractalkine receptor (CX₃CR1) could sensitize HR-proficient [...] Read more.

Background/Objectives: Clinical use of poly(ADP-ribose) polymerase inhibitors (PARPis) against metastatic high-grade serous ovarian carcinoma (HGSOC) is limited to cases with deficient a homologous recombination (HR). Our objective was to determine whether the impairment of the fractalkine receptor (CX₃CR1) could sensitize HR-proficient cases to PARPis. Methods: The efficacy of a dual drug combination, including AZD8797, an inhibitor of CX₃CR1, and several PARPis was examined using cell lines and xenograft models. Results: The effectiveness of PARPis and AZD8797 drug combinations ranged from additive to strongly synergistic. Olaparib was synergistic with AZD8797 in OVCAR-4, Caov-3, and OHSAHO. Niraparib and AZD8797 produced synergy in OVCAR-4 and ES2. Rucaparib and AZD8797 were strongly synergistic in Caov-3 and OVSAHO. Veliparib was strongly synergistic with AZD8797 in OVCAR-4 and Caov-3. Notably, a combination of veliparib and AZD8797 produced a strong synergistic effect in a xenograft model. Conclusions: While the exact mechanisms determining the nature of the PARPis and AZD8797 interaction remain to be uncovered, our data indicate that, in a subset of models, selected PARPis strongly synergize with the inhibition of CX₃CR1, suggesting a potential therapeutic opportunity. Full article

(This article belongs to the Special Issue Advances in Ovarian Cancer Research and Treatment)

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13 pages, 1132 KiB

Open AccessArticle

Zebrafish Avatars: Toward Functional Precision Medicine in Low-Grade Serous Ovarian Cancer

by Charlotte Fieuws, Jan Willem Bek, Bram Parton, Elyne De Neef, Olivier De Wever, Milena Hoorne, Marta F. Estrada, Jo Van Dorpe, Hannelore Denys, Koen Van de Vijver and Kathleen B. M. Claes

Cancers 2024, 16(10), 1812; https://doi.org/10.3390/cancers16101812 - 9 May 2024

Cited by 1 | Viewed by 1654

Abstract

Ovarian cancer (OC) is an umbrella term for cancerous malignancies affecting the ovaries, yet treatment options for all subtypes are predominantly derived from high-grade serous ovarian cancer, the largest subgroup. The concept of "functional precision medicine" involves gaining personalized insights on therapy choice, [...] Read more.

Ovarian cancer (OC) is an umbrella term for cancerous malignancies affecting the ovaries, yet treatment options for all subtypes are predominantly derived from high-grade serous ovarian cancer, the largest subgroup. The concept of "functional precision medicine" involves gaining personalized insights on therapy choice, based on direct exposure of patient tissues to drugs. This especially holds promise for rare subtypes like low-grade serous ovarian cancer (LGSOC). This study aims to establish an in vivo model for LGSOC using zebrafish embryos, comparing treatment responses previously observed in mouse PDX models, cell lines and 3D tumor models. To address this goal, a well-characterized patient-derived LGSOC cell line with the KRAS mutation c.35 G>T (p.(Gly12Val)) was used. Fluorescently labeled tumor cells were injected into the perivitelline space of 2 days’ post-fertilization zebrafish embryos. At 1 day post-injection, xenografts were assessed for tumor size, followed by random allocation into treatment groups with trametinib, luminespib and trametinib + luminespib. Subsequently, xenografts were euthanized and analyzed for apoptosis and proliferation by confocal microscopy. Tumor cells formed compact tumor masses (n = 84) in vivo, with clear Ki67 staining, indicating proliferation. Zebrafish xenografts exhibited sensitivity to trametinib and luminespib, individually or combined, within a two-week period, establishing them as a rapid and complementary tool to existing in vitro and in vivo models for evaluating targeted therapies in LGSOC. Full article

(This article belongs to the Special Issue Advances in Ovarian Cancer Research and Treatment)

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18 pages, 4673 KiB

Open AccessArticle

TIM3 Checkpoint Inhibition Fails to Prolong Survival in Ovarian Cancer-Bearing Mice

by Yani Berckmans, Ann Vankerckhoven, Aarushi Audhut Caro, Julie Kempeneers, Jolien Ceusters, Gitte Thirion, Katja Vandenbrande, Ignace Vergote, Damya Laoui and An Coosemans

Cancers 2024, 16(6), 1147; https://doi.org/10.3390/cancers16061147 - 14 Mar 2024

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Abstract

Immune checkpoint inhibitor (ICI) therapy has proven revolutionary in the treatment of some cancers. However, ovarian cancer remains unresponsive to current leading ICIs, such as anti-PD1 or anti-PD-L1. In this article, we explored the potential of an upcoming checkpoint molecule, T-cell immunoglobulin and [...] Read more.

Immune checkpoint inhibitor (ICI) therapy has proven revolutionary in the treatment of some cancers. However, ovarian cancer remains unresponsive to current leading ICIs, such as anti-PD1 or anti-PD-L1. In this article, we explored the potential of an upcoming checkpoint molecule, T-cell immunoglobulin and mucin domain 3 (TIM3), for the treatment of ovarian cancer using a syngeneic orthotopic mouse model (ID8-fLuc). Besides therapeutic efficacy, we focused on exploring immune changes in tumor tissue and peritoneal fluid. Our results showed no improvement in survival in ovarian cancer-bearing mice after anti-TIM3 treatment when used as monotherapy nor when combined with anti-PD1 or standard-of-care chemotherapy (carboplatin/paclitaxel). This was reflected in the unaltered immune infiltration in treated mice compared to control mice. Altering the order of drug administration within the combination treatment altered the survival results, but did not result in a survival benefit over chemotherapy alone. These findings highlight the need for further preclinical studies to find beneficial treatment schemes and combination therapies for ovarian cancer. Full article

(This article belongs to the Special Issue Advances in Ovarian Cancer Research and Treatment)

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12 pages, 2624 KiB

Open AccessArticle

Sexuality as a Prognostic Factor—Results of an Individual Patient Data NOGGO (North-Eastern German Society of Gynecological Oncology)-Meta-Analysis of 644 Recurrent Ovarian Cancer Patients Prior to Chemotherapy

by Nicole Balint, Hannah Woopen, Rolf Richter, Adak Pirmorady-Sehouli, Klaus Pietzner and Jalid Sehouli

Cancers 2024, 16(4), 811; https://doi.org/10.3390/cancers16040811 - 16 Feb 2024

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Abstract

Background: The aim of this study was to analyze the associations between sexuality, quality of life, treatment discontinuation, and survival in recurrent ovarian cancer (OC). Methods: Raw data from various phase II/III studies, including the questionnaires EORTC-QLQ-C30 and QLQ-OV28, were included. Data from [...] Read more.

Background: The aim of this study was to analyze the associations between sexuality, quality of life, treatment discontinuation, and survival in recurrent ovarian cancer (OC). Methods: Raw data from various phase II/III studies, including the questionnaires EORTC-QLQ-C30 and QLQ-OV28, were included. Data from the meta-analysis were calculated using logistic and Cox regression. Results: Data on sexuality were available for 644 patients. A total of 162 patients had an interest in sex and were sexually active (Group A). A total of 45 patients had an interest in sex and were sexually not active (Group I) and 437 patients had no interest in sex and were not sexually active (Group N). Group A was younger in median age (age at randomization), at 57 years, than Group I, at 60 years, and Group N, at 65 years (p < 0.001). Group A had a better ECOG performance status and fewer recurrences (all p < 0.001). FIGO stage, grading, and BMI were not associated with interest in sex and sexual activity. Group A showed higher scores in role, body, and social function (all p < 0.001), emotional functionality (p < 0.002), and body image (p = 0.012). In addition, Group A reported less pain, less peripheral neuropathy, and less fatigue (all p < 0.001). There was no association with the premature discontinuation of chemotherapy. Group A showed better survival rates compared to group N (22.3 months vs. 17.4 months, p < 0.001). Conclusions: Physicians should routinely address the topic of sexuality with ovarian cancer patients. Sexuality appears to be a marker for quality of life as well as overall survival. Full article

(This article belongs to the Special Issue Advances in Ovarian Cancer Research and Treatment)

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15 pages, 1555 KiB

Open AccessArticle

Pre-Operative Malnutrition in Patients with Ovarian Cancer: What Are the Clinical Implications? Results of a Prospective Study

by Sara Nasser, Esra Bilir, Xezal Derin, Rolf Richter, Jacek P. Grabowski, Paulina Ali, Hagen Kulbe, Radoslav Chekerov, Elena Braicu and Jalid Sehouli

Cancers 2024, 16(3), 622; https://doi.org/10.3390/cancers16030622 - 31 Jan 2024

Cited by 2 | Viewed by 1660

Abstract

Background: Malnutrition was associated with worse survival outcomes, impaired quality of life, and deteriorated performance status across various cancer types. We aimed to identify risk factors for malnutrition in patients with epithelial ovarian cancer (EOC) and impact on survival. Methods: In our prospective [...] Read more.

Background: Malnutrition was associated with worse survival outcomes, impaired quality of life, and deteriorated performance status across various cancer types. We aimed to identify risk factors for malnutrition in patients with epithelial ovarian cancer (EOC) and impact on survival. Methods: In our prospective observational monocentric study, we included the patients with primary and recurrent EOC, tubal or peritoneal cancer conducted. We assessed serum laboratory parameters, body mass index, nutritional risk index, nutritional risk screening score (NRS-2002), and bio-electrical impedance analysis. Results: We recruited a total of 152 patients. Patients > 65 years-old, with ascites of >500 mL, or with platinum-resistant EOC showed statistically significant increased risk of malnutrition when evaluated using NRS-2002 (p-values= 0.014, 0.001, and 0.007, respectively). NRS-2002 < 3 was an independent predictive factor for complete tumor resectability (p = 0.009). The patients with NRS-2002 ≥ 3 had a median overall survival (OS) of seven months (95% CI = 0–24 months), as compared to the patients with NRS-2002 < 3, where median OS was forty-six months (p = 0.001). A phase angle (PhAα) ≤ 4.5 was the strongest predictor of OS. Conclusions: In our study, we found malnutrition to be an independent predictor of incomplete cytoreduction and independent prognostic factor for poor OS. Preoperative nutritional assessment is an effective tool in the identification of high-risk EOC groups characterized by poor clinical outcome. Full article

(This article belongs to the Special Issue Advances in Ovarian Cancer Research and Treatment)

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14 pages, 3310 KiB

Open AccessArticle

Genetically Engineered Probiotic Limosilactobacillus reuteri Releasing IL-22 (LR-IL-22) Modifies the Tumor Microenvironment, Enabling Irradiation in Ovarian Cancer

by Diala F. Hamade, Michael W. Epperly, Renee Fisher, Wen Hou, Donna Shields, Jan-Peter van Pijkeren, Brian J. Leibowitz, Lan G. Coffman, Hong Wang, M. Saiful Huq, Ziyu Huang, Claude J. Rogers, Anda M. Vlad, Joel S. Greenberger and Amitava Mukherjee

Cancers 2024, 16(3), 474; https://doi.org/10.3390/cancers16030474 - 23 Jan 2024

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Abstract

Despite recent advances in cancer therapy, ovarian cancer remains the most lethal gynecological cancer worldwide, making it crucial and of the utmost importance to establish novel therapeutic strategies. Adjuvant radiotherapy has been assessed historically, but its use was limited by intestinal toxicity. We [...] Read more.

Despite recent advances in cancer therapy, ovarian cancer remains the most lethal gynecological cancer worldwide, making it crucial and of the utmost importance to establish novel therapeutic strategies. Adjuvant radiotherapy has been assessed historically, but its use was limited by intestinal toxicity. We recently established the role of Limosilactobacillus reuteri in releasing IL-22 (LR-IL-22) as an effective radiation mitigator, and we have now assessed its effect in an ovarian cancer mouse model. We hypothesized that an LR-IL-22 gavage would enable intestinal radioprotection by modifying the tumor microenvironment and, subsequently, improving overall survival in female C57BL/6MUC-1 mice with widespread abdominal syngeneic 2F8cis ovarian cancer. Herein, we report that the LR-IL-22 gavage not only improved overall survival in mice when combined with a PD-L1 inhibitor by inducing differential gene expression in irradiated stem cells but also induced PD-L1 protein expression in ovarian cancer cells and mobilized CD8+ T cells in whole abdomen irradiated mice. The addition of LR-IL-22 to a combined treatment modality with fractionated whole abdomen radiation (WAI) and systemic chemotherapy and immunotherapy regimens can facilitate a safe and effective protocol to reduce tumor burden, increase survival, and improve the quality of life of a locally advanced ovarian cancer patient. Full article

(This article belongs to the Special Issue Advances in Ovarian Cancer Research and Treatment)

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15 pages, 2348 KiB

Open AccessArticle

A Modified Basophil Activation Test for the Clinical Management of Immediate Hypersensitivity Reactions to Paclitaxel: A Proof-of-Concept Study

by Marilena La Sorda, Marco Fossati, Rosalia Graffeo, Manuela Ferraironi, Maria Cristina De Rosa, Alexia Buzzonetti, Benedetta Righino, Nicole Zampetti, Andrea Fattorossi, Eleonora Nucera, Arianna Aruanno, Gabriella Ferrandina, Adriana Ionelia Apostol, Alessandro Buonomo, Giovanni Scambia, Maurizio Sanguinetti and Alessandra Battaglia

Cancers 2023, 15(24), 5818; https://doi.org/10.3390/cancers15245818 - 13 Dec 2023

Cited by 2 | Viewed by 1586

Abstract

Immediate hypersensitivity reactions (iHSRs) to taxanes are observed in 6% and 4% of gynecologic and breast cancer patients, respectively. Drug desensitization is the only option, as no comparable alternative therapy is available. Surfactants in the taxane formulation have been implicated in the immunopathogenesis [...] Read more.

Immediate hypersensitivity reactions (iHSRs) to taxanes are observed in 6% and 4% of gynecologic and breast cancer patients, respectively. Drug desensitization is the only option, as no comparable alternative therapy is available. Surfactants in the taxane formulation have been implicated in the immunopathogenesis of iHSRs, although sporadic skin test (ST) positivity and iHSRs to nab-paclitaxel have suggested the involvement of the taxane moiety and/or IgE-mediated pathomechanisms. In vitro diagnostic tests might offer insights into mechanisms underlying iHSRs to taxanes. The aim of the present study was to address this unmet need by developing a novel basophil activation test (BAT). The study included patients (n = 31) undergoing paclitaxel/carboplatin therapy. Seventeen patients presented with iHSRs to paclitaxel (iHSR-Tax^pos), and eleven were tolerant (iHSR-Tax^neg). Fourteen patients presented with iHSRs to carboplatin (iHSR-Pl^pos), and fourteen were tolerant (iHSR-Pl^neg). The BAT median stimulation index (SI) values were 1.563 (range, 0.02–4.11; n = 11) and −0.28 (range −4.88–0.07, n = 11) in iHSR-Tax^pos and iHSR-Tax^neg, respectively. The BAT median SI values were 4.45 (range, 0.1–26.7; n = 14) and 0 (range, −0.51–1.65; n = 12) in iHSR-Pl^pos and iHSR-Pl^neg, respectively. SI levels were not associated with iHSR severity grading. Comparing BAT results in iHSR-Tax^pos and iHSR-Tax^neg showed the area under the receiver operator characteristic (ROC) curve to be 0.9752 (p = 0.0002). The cutoff calculated by the maximized likelihood ratio identified 90.91% of iHSR-Tax^pos patients and 90.91% of iHSR-Tax^neg patients. Comparing BAT results for iHSR-Pl^pos and iHSR-Pl^neg showed the area under the ROC curve to be 0.9286 (p = 0.0002). The cutoff calculated by the maximized likelihood ratio identified 78.57% of iHSR-Pl^pos patients and 91.67% of iHSR-Pl^neg patients. Most iHSR-Tax^pos patients for which ST was available (10/11) scored ST-negative and BAT-positive, whereas most iHSR-Pl^pos patients for which ST was available (14/14) scored both BAT- and ST-positive. This suggested the intervention of non-IgE-mediated mechanisms in iHSR-Tax^pos patients. Consistent with this view, an in silico molecular docking analysis predicted the high affinity of paclitaxel to the degranulation-competent MRGPRX2 receptor. This hypothesis warrants further in vitro investigations. In conclusion, the present study provides preliminary proof-of-concept evidence that this novel BAT has potential utility in understanding mechanisms underlying iHSRs to taxanes. Full article

(This article belongs to the Special Issue Advances in Ovarian Cancer Research and Treatment)

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12 pages, 396 KiB

Open AccessArticle

Is Cardiopulmonary Exercise Testing Predictive of Surgical Complications in Patients Undergoing Surgery for Ovarian Cancer?

by Anke Smits, Claire-Marie Agius, Dominic Blake, Christine Ang, Ali Kucukmetin, Maaike van Ham, Johanna M. A. Pijnenborg, Joanne Knight and Stuart Rundle

Cancers 2023, 15(21), 5185; https://doi.org/10.3390/cancers15215185 - 28 Oct 2023

Cited by 1 | Viewed by 1345

Abstract

Preoperative cardiopulmonary exercise testing (CPET) provides an objective assessment of functional capability. In other intra-abdominal surgical specialties, CPET outcomes are predictive of operative morbidity. However, in ovarian cancer surgery, its predictive value remains unknown. In this study, we evaluated the association between CPET [...] Read more.

Preoperative cardiopulmonary exercise testing (CPET) provides an objective assessment of functional capability. In other intra-abdominal surgical specialties, CPET outcomes are predictive of operative morbidity. However, in ovarian cancer surgery, its predictive value remains unknown. In this study, we evaluated the association between CPET performance and surgical morbidity in ovarian cancer patients. Secondly, we assessed the association between CPET performance and other surgical outcomes (i.e., hospital stay, readmission and residual disease). This was a retrospective cohort study of patients undergoing primary surgery for ovarian cancer between 2020 and 2023. CPET performance included peak oxygen uptake (VO₂ max), ventilatory efficiency (VE/VO₂) and anaerobic threshold. Outcomes were operative morbidity and included intra- and postoperative complications (Clavien–Dindo), hospital stay, readmission within 30 days and residual disease. A total of 142 patients were included. A lower VO₂ peak and a higher VE/VCO₂ were both associated with the occurrence of postoperative complications, and a poorer anaerobic threshold was associated with more transfusions. VE/VCO₂ remained significantly associated after multivariate analysis (p = 0.035). None of the CPET outcomes were associated with length of stay, readmission or residual disease. In conclusion, VE/VCO₂ was significantly associated with an increased risk of all-cause postoperative complications in ovarian cancer patients undergoing primary surgery. Full article

(This article belongs to the Special Issue Advances in Ovarian Cancer Research and Treatment)

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12 pages, 1041 KiB

Open AccessArticle

MAGE-A10 Protein Expression in Advanced High Grade Serous Ovarian Cancer Is Associated with Resistance to First-Line Platinum-Based Chemotherapy

by Nataša Lisica Šikić, Branka Petrić Miše, Snježana Tomić, Giulia Spagnol, Luka Matak, Antonio Juretić and Giulio Spagnoli

Cancers 2023, 15(19), 4697; https://doi.org/10.3390/cancers15194697 - 23 Sep 2023

Viewed by 1561

Abstract

Ovarian cancer has a dismal prognosis. Standard treatment following surgery relies on platinum-based chemotherapy. However, sizeable percentages of patients are unresponsive. Identification of markers predicting the response to chemotherapy might help select eligible patients and spare non-responding patients from treatment-associated toxicity. Cancer/testis antigens [...] Read more.

Ovarian cancer has a dismal prognosis. Standard treatment following surgery relies on platinum-based chemotherapy. However, sizeable percentages of patients are unresponsive. Identification of markers predicting the response to chemotherapy might help select eligible patients and spare non-responding patients from treatment-associated toxicity. Cancer/testis antigens (CTAs) are expressed by healthy germ cells and malignant cells of diverse histological origin. This expression profile identifies them as attractive targets for cancer immunotherapies. We analyzed the correlations between expression of MAGE-A10 and New York esophageal-1 cancer (NY-ESO-1) CTAs at the protein level and the effectiveness of platinum-based chemotherapy in patients with advanced-stage high-grade serous ovarian carcinoma (HGSOC). MAGE-A10 and NY-ESO-1 protein expression was analyzed by immunohistochemistry (IHC) in formalin-fixed, paraffin-embedded samples from 93 patients with advanced-stage HGSOC treated at our institutions between January 1996 and December 2013. The correlation between the expression of these markers and response to platinum-based chemotherapy, evaluated according to RECIST 1.1 criteria and platinum sensitivity, measured as platinum-free interval (PFI), progression free (PFS), and overall survival (OS) was explored. The MAGE-A10 protein expression predicted unresponsiveness to platinum-based chemotherapy (p = 0.005), poor platinum sensitivity (p < 0.001), poor PFS (p < 0.001), and OS (p < 0.001). Multivariate analysis identified MAGE-A10 protein expression as an independent predictor of poor platinum sensitivity (p = 0.005) and shorter OS (p < 0.001). Instead, no correlation was observed between the NY-ESO-1 protein expression and response to platinum-based chemotherapy (p = 0.832), platinum sensitivity (p = 0.168), PFS (p = 0.126), and OS (p = 0.335). The MAGE-A10 protein expression reliably identified advanced-stage HGSOC unresponsive to platinum-based chemotherapy. Targeted immunotherapy could represent an important alternative therapeutic option in these cancers. Full article

(This article belongs to the Special Issue Advances in Ovarian Cancer Research and Treatment)

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21 pages, 8217 KiB

Open AccessArticle

Integrated Multi-Omic Analysis Reveals Immunosuppressive Phenotype Associated with Poor Outcomes in High-Grade Serous Ovarian Cancer

by Russell Keathley, Masha Kocherginsky, Ramana Davuluri and Daniela Matei

Cancers 2023, 15(14), 3649; https://doi.org/10.3390/cancers15143649 - 17 Jul 2023

Cited by 3 | Viewed by 2161

Abstract

High-grade serous ovarian cancer (HGSOC) is characterized by a complex genomic landscape, with both genetic and epigenetic diversity contributing to its pathogenesis, disease course, and response to treatment. To better understand the association between genomic features and response to treatment among 370 patients [...] Read more.

High-grade serous ovarian cancer (HGSOC) is characterized by a complex genomic landscape, with both genetic and epigenetic diversity contributing to its pathogenesis, disease course, and response to treatment. To better understand the association between genomic features and response to treatment among 370 patients with newly diagnosed HGSOC, we utilized multi-omic data and semi-biased clustering of HGSOC specimens profiled by TCGA. A Cox regression model was deployed to select model input features based on the influence on disease recurrence. Among the features most significantly correlated with recurrence were the promotor-associated probes for the NFRKB and DPT genes and the TREML1 gene. Using 1467 transcriptomic and methylomic features as input to consensus clustering, we identified four distinct tumor clusters—three of which had noteworthy differences in treatment response and time to disease recurrence. Each cluster had unique divergence in differential analyses and distinctly enriched pathways therein. Differences in predicted stromal and immune cell-type composition were also observed, with an immune-suppressive phenotype specific to one cluster, which associated with short time to disease recurrence. Our model features were additionally used as a neural network input layer to validate the previously defined clusters with high prediction accuracy (91.3%). Overall, our approach highlights an integrated data utilization workflow from tumor-derived samples, which can be used to uncover novel drivers of clinical outcomes. Full article

(This article belongs to the Special Issue Advances in Ovarian Cancer Research and Treatment)

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14 pages, 6680 KiB

Open AccessArticle

Trends in Systemic Inflammatory Reaction (SIR) during Paclitaxel and Carboplatin Chemotherapy in Women Suffering from Epithelial Ovarian Cancer

by Michal Mleko, Elzbieta Pluta, Kazimierz Pitynski, Maciej Bodzek, Andrzej Kałamacki, Dorota Kiprian and Tomasz Banas

Cancers 2023, 15(14), 3607; https://doi.org/10.3390/cancers15143607 - 13 Jul 2023

Cited by 1 | Viewed by 1458

Abstract

Background: Epithelial ovarian cancer (EOC) is the most fatal gynaecological malignancy treated with cytoreductive surgery followed by adjuvant taxane-platinum-based chemotherapy. It has been shown that the pretreatment systemic inflammatory reaction (SIR) in women with OC can be evaluated using the neutrophil-to-lymphocyte ratio (NLR), [...] Read more.

Background: Epithelial ovarian cancer (EOC) is the most fatal gynaecological malignancy treated with cytoreductive surgery followed by adjuvant taxane-platinum-based chemotherapy. It has been shown that the pretreatment systemic inflammatory reaction (SIR) in women with OC can be evaluated using the neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR) and systemic inflammatory index (SII), depending on the stage of disease, and has prognostic value for overall survival. The aim of this study was to evaluate the changes in NLR, LMR, PLR and SII during chemotherapy. Methods: A total of 107 women with EOC (23 with type I and 84 with type II tumours) were included in a retrospective single-centre analysis. The Kologomorov−Smirnoff, Kruskal-Wallis or Friedman analysis of variance tests were used for data analysis, and a p value of 0.05 was considered statistically significant. Results: A significant decrease in NLR, PLR and SII but not LMR was observed during adjuvant treatment. Pretreatment NLR, PLR and SII were dependent on disease stage and tumour grade; however, this association was lost during therapy. Additionally, strong and positive mutual correlations between NLR, LMR, PLR and SII were sustained during the whole course of chemotherapy. Conclusions: During first-line adjuvant chemotherapy in women with EOC, a decrease in SIR is confirmed. Full article

(This article belongs to the Special Issue Advances in Ovarian Cancer Research and Treatment)

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9 pages, 656 KiB

Open AccessArticle

A Retrospective Study Comparing Olaparib and Bevacizumab as a Maintenance Therapy for Platinum-Sensitive Recurrent Ovarian Cancer: Impact on Recurrence-Free Survival in Japanese and Asian Populations

by Kazuho Nakanishi, Masafumi Toyoshima, Yuta Ueno and Shunji Suzuki

Cancers 2023, 15(10), 2869; https://doi.org/10.3390/cancers15102869 - 22 May 2023

Cited by 1 | Viewed by 1838

Abstract

The use of angiogenesis inhibitors and poly ADP-ribose polymerase inhibitors following multi-agent chemotherapy, including platinum-based agents, has become the standard treatment for platinum-sensitive recurrent ovarian cancer (PSROC). However, the optimal maintenance therapy and selection criteria for these patients remain unclear. Thus, this study [...] Read more.

The use of angiogenesis inhibitors and poly ADP-ribose polymerase inhibitors following multi-agent chemotherapy, including platinum-based agents, has become the standard treatment for platinum-sensitive recurrent ovarian cancer (PSROC). However, the optimal maintenance therapy and selection criteria for these patients remain unclear. Thus, this study aimed to optimize the treatment options and selection criteria for patients with PSROC. The clinical data of 51 patients with PSROC admitted to Nippon Medical School Chiba Hokusoh Hospital and Nippon Medical School Hospital were retrospectively collected. The log-rank test was used for the survival analysis, and Cox proportional hazard regression analysis was used for the multivariate survival analysis. Of the 51 patients, 17 received maintenance therapy with bevacizumab (Bev), and 34 received olaparib (Ola). Recurrence-free survival (RFS) was significantly prolonged in the Ola group (27 months; 95% confidence interval (CI), 19–NA months) compared with that in the Bev group (9 months; 95% CI, 5–22 months; p = 0.000103). The efficacy of Ola was independent of background factors, including response to previous chemotherapy, homologous recombination status, histological type, or laboratory data. Ola is superior to Bev as PSROC maintenance therapy, especially in Japanese and Asian populations. Full article

(This article belongs to the Special Issue Advances in Ovarian Cancer Research and Treatment)

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13 pages, 2495 KiB

Open AccessArticle

Exploring the Control of PARP1 Levels in High-Grade Serous Ovarian Cancer

by Giuseppina Raspaglio, Marianna Buttarelli, Natalia Cappoli, Alessandra Ciucci, Anna Fagotti, Giovanni Scambia and Daniela Gallo

Cancers 2023, 15(8), 2361; https://doi.org/10.3390/cancers15082361 - 18 Apr 2023

Viewed by 2050

Abstract

High-grade serous ovarian cancer (HGSOC) is a leading cause of mortality from gynecologic malignancies worldwide. Although a transformative improvement has been shown with the introduction of PARP (poly(ADP-ribose) polymerase) inhibitors, the emergence of resistance to these drugs represents a therapeutic challenge. Hence, expanding [...] Read more.

High-grade serous ovarian cancer (HGSOC) is a leading cause of mortality from gynecologic malignancies worldwide. Although a transformative improvement has been shown with the introduction of PARP (poly(ADP-ribose) polymerase) inhibitors, the emergence of resistance to these drugs represents a therapeutic challenge. Hence, expanding our understanding of mechanisms behind the control of PARP1 expression can provide strategic guidance for the translation of novel therapeutic strategies. The Signal Transducer and Activator of Transcription (STAT) family of proteins consists of transcription factors critically involved in the regulation of important cellular functions. Notably, we recently demonstrated that, in cervical cancer cells, STAT1 controls PARP1 levels through multiple mechanisms, possibly involving also STAT3. Here, we tested the hypothesis that a similar mechanism might be operative in HGSOC. To this end, the impact of STAT1/STAT3 modulation on PARP1 expression was assessed in established and primary HGSOC cells, and molecular biology studies proved that STAT1 might act at both transcriptional and post-transcriptional levels to modulate the PARP1 level. Notably, bioinformatics analysis of TCGA databases demonstrated that increased STAT1 mRNA expression levels are associated with a favorable prognosis and with response to chemotherapy in HGSOC patients. Our findings suggest an alternative strategy for targeting HGSOC cells based on their dependency on PARP1. Full article

(This article belongs to the Special Issue Advances in Ovarian Cancer Research and Treatment)

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15 pages, 2911 KiB

Open AccessArticle

Increased Local Testosterone Levels Alter Human Fallopian Tube mRNA Profile and Signaling

by Angela Russo, Brian P. Cain, Tia Jackson-Bey, Alfredo Lopez Carrero, Jane Miglo, Shannon MacLaughlan, Brett C. Isenberg, Jonathan Coppeta and Joanna E. Burdette

Cancers 2023, 15(7), 2062; https://doi.org/10.3390/cancers15072062 - 30 Mar 2023

Cited by 2 | Viewed by 2216

Abstract

Fallopian tube epithelium (FTE) plays a critical role in reproduction and can be the site where High Grade Serous Ovarian Carcinoma (HGSOC) originates. Tumorigenic oviductal cells, which are the murine equivalent of human fallopian tube secretory epithelial cells (FTSEC), enhance testosterone secretion by [...] Read more.

Fallopian tube epithelium (FTE) plays a critical role in reproduction and can be the site where High Grade Serous Ovarian Carcinoma (HGSOC) originates. Tumorigenic oviductal cells, which are the murine equivalent of human fallopian tube secretory epithelial cells (FTSEC), enhance testosterone secretion by the ovary when co-cultured with the ovary, suggesting that testosterone is part of the signaling axis between the ovary and FTSEC. Furthermore, testosterone promotes proliferation of oviductal cells. Oral contraceptives, tubal ligation, and salpingectomy, which are all protective against developing ovarian cancer, also decrease circulating levels of androgen. In the current study, we investigated the effect of increased testosterone on FTE and found that testosterone upregulates wingless-type MMTV integration family, member 4 (WNT4) and induces migration and invasion of immortalized human fallopian tube cells. We profiled primary human fallopian tissues grown in the microfluidic system SOLO-microfluidic platform –(MFP) by RNA sequencing and found that p53 and its downstream target genes, such as paired box gene 2 (PAX2), cyclin-dependent kinase inhibitor 1A (CDK1A or p21), and cluster of differentiation 82 (CD82 or KAI1) were downregulated in response to testosterone treatment. A microfluidic platform, the PREDICT-Multi Organ System (PREDICT-MOS) was engineered to support insert technology that allowed for the study of cancer cell migration and invasion through Matrigel. Using this system, we found that testosterone enhanced FTE migration and invasion, which was reversed by the androgen receptor (AR) antagonist, bicalutamide. Testosterone also enhanced FTSEC adhesion to the ovarian stroma using murine ovaries. Overall, these results indicate that primary human fallopian tube tissue and immortalized FTSEC respond to testosterone to shift expression of genes that regulate invasion, while leveraging a new strategy to study migration in the presence of dynamic fluid flow. Full article

(This article belongs to the Special Issue Advances in Ovarian Cancer Research and Treatment)

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9 pages, 404 KiB

Open AccessCommunication

Identifying Borderline Ovarian Tumor Recurrence Using Routine Ultrasound Follow-Up

by Caitlin Lazurko, Tomer Feigenberg, Joan Murphy, Kate Pulman, Genevieve Lennox, Valerie Dube and Tiffany Zigras

Cancers 2023, 15(1), 73; https://doi.org/10.3390/cancers15010073 - 22 Dec 2022

Cited by 1 | Viewed by 2414

Abstract

Borderline ovarian tumors (BOTs) are non-invasive tumors frequently diagnosed in young patients. Surgical removal of the uterus, fallopian tubes, ovaries, and omentum is considered definitive management, however fertility-sparing approach is a recognized option. Surveillance is important due to known recurrence, but there is [...] Read more.

Borderline ovarian tumors (BOTs) are non-invasive tumors frequently diagnosed in young patients. Surgical removal of the uterus, fallopian tubes, ovaries, and omentum is considered definitive management, however fertility-sparing approach is a recognized option. Surveillance is important due to known recurrence, but there is controversy over the effectiveness of follow-up modalities. The objective is to determine the efficacy of ultrasound screening in identifying tumor recurrence. This retrospective chart review evaluated all patients consulted and/or treated surgically at our institution from January 2015 to June 2020 diagnosed with BOT. Patients were excluded if concurrently diagnosed with another gynecologic malignancy, did not have yearly ultrasound follow-up, or were lost to follow-up. This study included 56 patients, 17 of whom underwent fertility preserving surgery. The overall rate of recurrence was 10.7%; with recurrence rates of 23.5% for the fertility preserving surgery population and 5.1% for the definitive surgery population. Ultrasound first identified 5 of the 6 (83.3%) recurrences. Overall time to recurrence was 51.5 months. In conclusion, recurrences were identified on routine ultrasound screening prior to symptom onset or detection via physical exam in 83.3% of cases. While the best modality of follow-up remains controversial, this review provides evidence supporting the use of routine ultrasound follow-up for early detection of BOT recurrence. Full article

(This article belongs to the Special Issue Advances in Ovarian Cancer Research and Treatment)

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Review

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22 pages, 8565 KiB

Open AccessReview

Ovarian Causes of Pseudomyxoma Peritonei (PMP)—A Literature Review

by Sinziana Ionescu, Marian Marincas, Octavia Luciana Madge, Irinel Gabriel Dicu-Andreescu, Elena Chitoran, Vlad Rotaru, Ciprian Cirimbei, Mirela Gherghe, Adina Ene, Robert Rosca, Madalina Radu and Laurentiu Simion

Cancers 2024, 16(8), 1446; https://doi.org/10.3390/cancers16081446 - 9 Apr 2024

Cited by 4 | Viewed by 2815

Abstract

Background. Pseudomyxoma peritonei (PMP) is a rare, progressive, slowly growing, inadequately understood neoplasm with a 5-year progression-free survival rate of as low as 48%. It is characterized by varying degrees of malignancy and the production of mucinous and gelatinous structures. Typically, the development [...] Read more.

Background. Pseudomyxoma peritonei (PMP) is a rare, progressive, slowly growing, inadequately understood neoplasm with a 5-year progression-free survival rate of as low as 48%. It is characterized by varying degrees of malignancy and the production of mucinous and gelatinous structures. Typically, the development of pseudomyxoma peritonei is associated with the rupture of appendiceal mucinous tumors and other gastrointestinal or ovarian mucinous tumors. The goal of our literature review was to identify various aspects that characterize the ovarian causes of pseudomyxoma peritonei. Materials and methods. The authors performed an extensive literature search between 1 February 2024 and 2 March 2024 on the following databases: Pubmed, Scopus, Oxford Journals, and Reaxys, and the findings were summarized into seven main clinical and paraclinical situations. Results. According to our research, the main instances in which pseudomyxoma peritonei can be triggered by an ovarian cause are the following: (1) mucinous cystadenoma; (2) mucinous ovarian cancer; (3) colon cancer with ovarian metastasis; (4) malignant transformation of an ovarian primary mature cystic teratoma; (5) appendiceal mucocele with peritoneal dissemination mimicking an ovarian tumor with peritoneal carcinomatosis; (6) mucinous borderline tumor developing inside an ovarian teratoma; and (7) the association between a mucinous bilateral ovarian cancer and a colonic tumor. Conclusions. In our study, we aimed to provide a comprehensive overview of the ovarian causes of pseudomyxoma peritonei, including its epidemiology, imagery characteristics, symptoms, current treatment, and promising future therapies, in the hopes of finding feasible solutions, as a lack of understanding of this mucus-secreting malignant disease increases the risk of delayed diagnosis or uncontrolled deterioration. Full article

(This article belongs to the Special Issue Advances in Ovarian Cancer Research and Treatment)

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29 pages, 3011 KiB

Open AccessReview

Unveiling the Immunogenicity of Ovarian Tumors as the Crucial Catalyst for Therapeutic Success

by Galaxia M. Rodriguez, Edward Yakubovich and Barbara C. Vanderhyden

Cancers 2023, 15(23), 5694; https://doi.org/10.3390/cancers15235694 - 2 Dec 2023

Cited by 2 | Viewed by 2509

Abstract

Epithelial ovarian cancer (EOC) is the most lethal gynecologic cancer. The disease is often diagnosed after wide-spread dissemination, and the standard treatment combines aggressive surgery with platinum-based chemotherapy; however, most patients experience relapse in the form of peritoneal carcinomatosis, resulting in a 5-year [...] Read more.

Epithelial ovarian cancer (EOC) is the most lethal gynecologic cancer. The disease is often diagnosed after wide-spread dissemination, and the standard treatment combines aggressive surgery with platinum-based chemotherapy; however, most patients experience relapse in the form of peritoneal carcinomatosis, resulting in a 5-year mortality below 45%. There is clearly a need for the development of novel treatments and cancer immunotherapies offering a different approach. Immunotherapies have demonstrated their efficacy in many types of cancers; however, only <15% of EOC patients show any evidence of response. One of the main barriers behind the poor therapeutic outcome is the reduced expression of Major Histocompatibility Complexes class I (MHC I) which occurs in approximately 60% of EOC cases. This review aims to gather and enhance our current understanding of EOC, focusing on its distinct cancer characteristics related to MHC I expression, immunogenicity, antigen presentation, epithelial-to-mesenchymal transition, and various ongoing immunotherapeutic strategies designed to stimulate antitumor immunity. Full article

(This article belongs to the Special Issue Advances in Ovarian Cancer Research and Treatment)

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10 pages, 258 KiB

Open AccessReview

To Bev or Not to Bev during Ovarian Cancer Maintenance Therapy?

by Jacek Jan Sznurkowski

Cancers 2023, 15(11), 2980; https://doi.org/10.3390/cancers15112980 - 30 May 2023

Cited by 5 | Viewed by 2895

Abstract

Background: Maintenance therapy with PARP inhibitors and bevacizumab is approved for ovarian cancer treatment in the first and second line settings, but selecting the optimal sequence is challenging due to restrictions on using the same medication twice. This review aims to establish guidelines [...] Read more.

Background: Maintenance therapy with PARP inhibitors and bevacizumab is approved for ovarian cancer treatment in the first and second line settings, but selecting the optimal sequence is challenging due to restrictions on using the same medication twice. This review aims to establish guidelines for ovarian cancer maintenance therapy based on the strength of scientific evidence, the most effective treatment strategy, and the impact on the healthcare system. Methods: Six questions were formulated to evaluate the scientific evidence supporting different maintenance therapy options using the AGREE II guideline evaluation tool. The questions address the acceptability of reusing the same medication, the efficacy of bevacizumab and PARP inhibitors in the first and second line settings, the comparative efficacy of these medications, the potential benefit of combination maintenance therapy, and the economic impact of maintenance therapy. Results: Based on the available evidence, bevacizumab should be preserved for second line maintenance therapy, and maintenance therapy with PARP inhibitors should be offered to all advanced ovarian cancer patients who have responded to first line platinum-based chemotherapy. Additional molecular predictors for bevacizumab efficacy are needed. Conclusions: The presented guidelines offer an evidence-based framework for selecting the most effective maintenance therapy for ovarian cancer patients. Further research is necessary to refine these recommendations and improve outcomes for patients with this disease. Full article

(This article belongs to the Special Issue Advances in Ovarian Cancer Research and Treatment)

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