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17 pages, 1822 KiB

Open AccessArticle

Combining ReACp53 with Carboplatin to Target High-Grade Serous Ovarian Cancers

by Adam Neal, Tiffany Lai, Tanya Singh, Neela Rahseparian, Tristan Grogan, David Elashoff, Peter Scott, Matteo Pellegrini and Sanaz Memarzadeh

Cancers 2021, 13(23), 5908; https://doi.org/10.3390/cancers13235908 - 24 Nov 2021

Cited by 12 | Viewed by 2561

Abstract

Ovarian malignancies are a leading cause of cancer-related death for US women. High-grade serous ovarian carcinomas (HGSOCs), the most common ovarian cancer subtype, are aggressive tumors with poor outcomes. Mutations in TP53 are common in HGSOCs, with a subset resulting in p53 aggregation [...] Read more.

Ovarian malignancies are a leading cause of cancer-related death for US women. High-grade serous ovarian carcinomas (HGSOCs), the most common ovarian cancer subtype, are aggressive tumors with poor outcomes. Mutations in TP53 are common in HGSOCs, with a subset resulting in p53 aggregation and misregulation. ReACp53 is a peptide designed to inhibit mutant p53 aggregation and has been shown efficacious in targeting cancer cells in vitro and in vivo. As p53 regulates apoptosis, combining ReACp53 with carboplatin represents a logical therapeutic strategy. The efficacy of this combinatorial approach was tested in eight ovarian cancer cell lines and 10 patient HGSOC samples using an in vitro organoid drug assay, with the SynergyFinder tool utilized for calculating drug interactions. Results demonstrate that the addition of ReACp53 to carboplatin enhanced tumor cell targeting in the majority of samples tested, with synergistic effects measured in 2 samples, additivity measured in 14 samples, and antagonism measured in 1 sample. This combination was found to be synergistic in OVCAR3 ovarian cancer cells in vitro through enhanced apoptosis, and survival of mice bearing OVCAR3 intraperitoneal xenografts was extended when treated with the addition of ReACp53 to carboplatin versus carboplatin alone. Results suggest that carboplatin and ReACp53 may be a potential strategy in targeting a subset of HGSOCs. Full article

(This article belongs to the Special Issue High-Grade Serous Ovarian Cancer)

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12 pages, 238 KiB

Open AccessArticle

Antihypertensive Drug Use and the Risk of Ovarian Cancer Death among Finnish Ovarian Cancer Patients—A Nationwide Cohort Study

by Eerik E. E. Santala, Miia Artama, Eero Pukkala, Kala Visvanathan, Synnöve Staff and Teemu J. Murtola

Cancers 2021, 13(9), 2087; https://doi.org/10.3390/cancers13092087 - 26 Apr 2021

Cited by 6 | Viewed by 1978

Abstract

Ovarian cancer (OC) has a poor prognosis. Hypertension may be a prognostic factor for OC, but it is unclear whether antihypertensive (anti-HT) drug use of modifies OC prognosis. We performed a population-based analysis assessing the effect of anti-HT drug use on OC mortality. [...] Read more.

Ovarian cancer (OC) has a poor prognosis. Hypertension may be a prognostic factor for OC, but it is unclear whether antihypertensive (anti-HT) drug use of modifies OC prognosis. We performed a population-based analysis assessing the effect of anti-HT drug use on OC mortality. A cohort of 12,122 women identified from the Finnish Cancer Registry with OC in 1995–2013 was combined with information on their anti-HT drug use during the same time period. Use of each anti-HT drug was analysed as a time-dependent variable. Analyses were run for five, ten and full follow-up (19-year) mortality with cardiovascular morbidity risk evaluated in competing risk analysis. No anti-HT drug group was associated with OC survival within five years after OC diagnosis. At ten years, a dose-dependent association was observed between pre-diagnostic ACE-inhibitor use and improved OC survival. With full follow-up, post-diagnostic high-intensity use associated with reduced OC death risk for multiple anti-HT drug groups. In competing risk analysis, only the post-diagnostic use of ACE-inhibitors associated with increased OC survival. Anti-HT drugs were not associated with survival benefits within five years after OC diagnosis. ACE-inhibitors may confer survival benefits in women with OC, but further confirmatory studies are needed. Full article

(This article belongs to the Special Issue High-Grade Serous Ovarian Cancer)

22 pages, 5845 KiB

Open AccessArticle

RUNX3 Transcript Variants Have Distinct Roles in Ovarian Carcinoma and Differently Influence Platinum Sensitivity and Angiogenesis

by Karolin Heinze, Martin Hölzer, Martin Ungelenk, Melanie Gerth, Jürgen Thomale, Regine Heller, Claire R. Morden, Kirk J. McManus, Alexander S. Mosig, Matthias Dürst, Ingo B. Runnebaum and Norman Häfner

Cancers 2021, 13(3), 476; https://doi.org/10.3390/cancers13030476 - 26 Jan 2021

Cited by 4 | Viewed by 2430

Abstract

The prognosis of late-stage epithelial ovarian cancer (EOC) patients is affected by chemotherapy response and the malignant potential of the tumor cells. In earlier work, we identified hypermethylation of the runt-related transcription factor 3 gene (RUNX3) as a prognostic biomarker and [...] Read more.

The prognosis of late-stage epithelial ovarian cancer (EOC) patients is affected by chemotherapy response and the malignant potential of the tumor cells. In earlier work, we identified hypermethylation of the runt-related transcription factor 3 gene (RUNX3) as a prognostic biomarker and contrary functions of transcript variants (TV1 and TV2) in A2780 and SKOV3 cells. The aim of the study was to further validate these results and to increase the knowledge about RUNX3 function in EOC. New RUNX3 overexpression models of high-grade serous ovarian cancer (HGSOC) were established and analyzed for phenotypic (IC₅₀ determination, migration, proliferation and angiogenesis assay, DNA damage analysis) and transcriptomic consequences (NGS) of RUNX3 TV1 and TV2 overexpression. Platinum sensitivity was affected by a specific transcript variant depending on BRCA background. RUNX3 TV2 induced an increased sensitivity in BRCA1^wt cells (OVCAR3), whereas TV1 increased the sensitivity and induced a G2/M arrest under treatment in BRCA1^mut cells (A13-2-12). These different phenotypes relate to differences in DNA repair: homologous recombination deficient A13-2-12 cells show less γH2AX foci despite higher levels of Pt-DNA adducts. RNA-Seq analyses prove transcript variant and cell-line-specific RUNX3 effects. Pathway analyses revealed another clinically important function of RUNX3—regulation of angiogenesis. This was confirmed by thrombospondin1 analyses, HUVEC spheroid sprouting assays and proteomic profiling. Importantly, conditioned media (CM) from RUNX3 TV1 overexpressing A13-2-12 cells induced an increased HUVEC sprouting. Altogether, the presented data support the hypothesis of different functions of RUNX3 transcript variants related to the clinically relevant processes—platinum resistance and angiogenesis. Full article

(This article belongs to the Special Issue High-Grade Serous Ovarian Cancer)

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20 pages, 5413 KiB

Open AccessArticle

Convergence of Plasma Metabolomics and Proteomics Analysis to Discover Signatures of High-Grade Serous Ovarian Cancer

by Hee-Sung Ahn, Jeonghun Yeom, Jiyoung Yu, Young-Il Kwon, Jae-Hoon Kim and Kyunggon Kim

Cancers 2020, 12(11), 3447; https://doi.org/10.3390/cancers12113447 - 19 Nov 2020

Cited by 26 | Viewed by 4321

Abstract

The 5-year survival rate in the early and late stages of ovarian cancer differs by 63%. In addition, a liquid biopsy is necessary because there are no symptoms in the early stage and tissue collection is difficult without using invasive methods. Therefore, there [...] Read more.

The 5-year survival rate in the early and late stages of ovarian cancer differs by 63%. In addition, a liquid biopsy is necessary because there are no symptoms in the early stage and tissue collection is difficult without using invasive methods. Therefore, there is a need for biomarkers to achieve this goal. In this study, we found blood-based metabolite or protein biomarker candidates for the diagnosis of ovarian cancer in the 20 clinical samples (10 ovarian cancer patients and 10 healthy control subjects). Plasma metabolites and proteins were measured and quantified using mass spectrometry in ovarian cancer patients and control groups. We identified the differential abundant biomolecules (34 metabolites and 197 proteins) and statistically integrated molecules of different dimensions to better understand ovarian cancer signal transduction and to identify novel biological mechanisms. In addition, the biomarker reliability was verified through comparison with existing research results. Integrated analysis of metabolome and proteome identified emerging properties difficult to grasp with the single omics approach, more reliably interpreted the cancer signaling pathway, and explored new drug targets. Especially, through this analysis, proteins (PPCS, PMP2, and TUBB) and metabolites (L-carnitine and PC-O (30:0)) related to the carnitine system involved in cancer plasticity were identified. Full article

(This article belongs to the Special Issue High-Grade Serous Ovarian Cancer)

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16 pages, 2211 KiB

Open AccessArticle

Signal Transduction Pathway Activity in High-Grade, Serous Ovarian Carcinoma Reveals a More Favorable Prognosis in Tumors with Low PI3K and High NF-κB Pathway Activity: A Novel Approach to a Long-Standing Enigma

by Laura van Lieshout, Anja van de Stolpe, Phyllis van der Ploeg, David Bowtell, Joanne de Hullu and Jurgen Piek

Cancers 2020, 12(9), 2660; https://doi.org/10.3390/cancers12092660 - 18 Sep 2020

Cited by 8 | Viewed by 2438

Abstract

We investigated signal transduction pathway (STP) activity in high-grade serous ovarian carcinoma (HGSC) in relation to progression-free survival (PFS) and overall survival (OS). We made use of signal transduction pathway activity analysis (STA analysis), a novel method to quantify functional STP activity. Activity [...] Read more.

We investigated signal transduction pathway (STP) activity in high-grade serous ovarian carcinoma (HGSC) in relation to progression-free survival (PFS) and overall survival (OS). We made use of signal transduction pathway activity analysis (STA analysis), a novel method to quantify functional STP activity. Activity of the following pathways was measured: androgen receptor (AR), estrogen receptor (ER), phosphoinositide 3-kinase (PI3K), Hedgehog (Hh), Notch, nuclear factor-kappa B (NF-κB), transforming growth factor beta (TGF-β), and Wnt. We selected HGSC samples from publicly available datasets of ovarian cancer tissue, and used repeated k-means clustering to identify pathway activity clusters. PFS and OS of the clusters were analyzed. We used a subset of publicly available dataset GSE9891 (n = 140), where repeated k-means clustering based on PI3K and NF-κB pathway activity in HGSC samples resulted in two stable clusters. The cluster with low PI3K and high NF-κB pathway activity (n = 72) had a more favorable prognosis for both PFS (p = 0.004) and OS (p = 0.001) compared to the high-PI3K and low-NF-κB pathway activity cluster (n = 68). The low PI3K and high NF-κB pathway activity of the favorable prognosis cluster may indicate a more active immune response, while the high PI3K and low NF-κB pathway activity of the unfavorable prognosis cluster may indicate high cell division. Full article

(This article belongs to the Special Issue High-Grade Serous Ovarian Cancer)

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11 pages, 957 KiB

Open AccessArticle

Cytoreductive Surgery for Heavily Pre-Treated, Platinum-Resistant Epithelial Ovarian Carcinoma: A Two-Center Retrospective Experience

by Valentina Tuninetti, Marilena Di Napoli, Eleonora Ghisoni, Furio Maggiorotto, Manuela Robella, Giulia Scotto, Gaia Giannone, Margherita Turinetto, Dimitris Siatis, Riccardo Ponzone, Marco Vaira, Michele De Simone, Cono Scaffa, Sandro Pignata, Stefano Greggi, Massimo Di Maio and Giorgio Valabrega

Cancers 2020, 12(8), 2239; https://doi.org/10.3390/cancers12082239 - 10 Aug 2020

Cited by 5 | Viewed by 2481

Abstract

Few retrospective studies have shown a benefit in selected patients affected by heavily pre-treated, platinum-resistant ovarian carcinomas (PROCs) who have undergone cytoreduction at relapse. However, the role of tertiary and quaternary cytoreductive surgery is not fully defined. Our aim was to evaluate survival [...] Read more.

Few retrospective studies have shown a benefit in selected patients affected by heavily pre-treated, platinum-resistant ovarian carcinomas (PROCs) who have undergone cytoreduction at relapse. However, the role of tertiary and quaternary cytoreductive surgery is not fully defined. Our aim was to evaluate survival and surgical morbidity and mortality after maximal cytoreduction in this setting. We evaluated all consecutive patients undergoing cytoreduction for platinum-resistance over an 8-year period (2010–2018) in two different centers. Fifty patients (median age 52.5 years, range 34–75) were included; the median number of previous chemotherapy lines was three (range 1–7) and the median number of previous surgeries was one (range 1–4). Completeness of cytoreduction (CC = 0) was achieved in 22 patients (44%). Rates of major operative morbidity and 30-day mortality were 38% and 8%, respectively. Median follow-up was 35 months. The absence of tumor residual (CC = 0) was associated with a significantly better overall survival (OS) compared to the CC > 0 subgroup (median OS 32.9 months (95% CI 21.6–44.2) vs. 4.8 months (95% CI n.a.–9.8), hazard ratio (HR) 4.21 (95% CI 2.07–8.60), p < 0.001). Optimal cytoreduction is feasible and associated with promising OS in selected, heavily pre-treated PROCs. Further prospective studies are required to better define the role of surgery in platinum-resistant disease. Full article

(This article belongs to the Special Issue High-Grade Serous Ovarian Cancer)

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Review

Jump to: Research

15 pages, 1345 KiB

Open AccessReview

Risk of Thrombo-Embolic Events in Ovarian Cancer: Does Bevacizumab Tilt the Scale? A Systematic Review and Meta-Analysis

by Michael Saerens, Emiel A. De Jaeghere, Heini Kanervo, Nele Vandemaele, Hannelore Denys and Eline Naert

Cancers 2021, 13(18), 4603; https://doi.org/10.3390/cancers13184603 - 14 Sep 2021

Cited by 12 | Viewed by 2664

Abstract

Thromboembolic events are the second cause of death in cancer patients. In ovarian cancer, 3–10% of patients present with venous thromboembolism (VTE), but the incidence may rise to 36% along the disease course. Bevacizumab is a monoclonal antibody directed against vascular endothelial-derived growth [...] Read more.

Thromboembolic events are the second cause of death in cancer patients. In ovarian cancer, 3–10% of patients present with venous thromboembolism (VTE), but the incidence may rise to 36% along the disease course. Bevacizumab is a monoclonal antibody directed against vascular endothelial-derived growth factor, and in in vitro studies it showed a predisposition to hemostasis perturbation, including thrombosis. However, in vivo and clinical studies have shown conflicting results for its use as a treatment for ovarian cancer, so we conducted a systematic review and meta-analysis on the risk of arterial thromboembolism (ATE) and VTE in ovarian cancer patients treated with bevacizumab. The review comprised 14 trials with 6221 patients: ATE incidence was reported in 5 (4811 patients) where the absolute risk was 2.4% with bevacizumab vs. 1.1% without (RR 2.45; 95% CI 1.27–4.27, p = 0.008). VTE incidence was reported in 9 trials (5121 patients) where the absolute risk was 5.4% with bevacizumab vs. 3.7% without (RR 1.32; 95% CI 1.02–1.79, p = 0.04). Our analysis showed that the risk of arterial and venous thromboembolism increased in patients treated with bevacizumab. Thrombolic events (TEs) are probably underreported, and studies should discriminate between ATE and VTE. Bevacizumab can be considered as an additional risk factor when selecting patients for primary prophylaxis with anticoagulants. Full article

(This article belongs to the Special Issue High-Grade Serous Ovarian Cancer)

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21 pages, 1009 KiB

Open AccessReview

Mutated p53 in HGSC—From a Common Mutation to a Target for Therapy

by Aya Saleh and Ruth Perets

Cancers 2021, 13(14), 3465; https://doi.org/10.3390/cancers13143465 - 10 Jul 2021

Cited by 12 | Viewed by 3895

Abstract

Mutations in tumor suppressor gene TP53, encoding for the p53 protein, are the most ubiquitous genetic variation in human ovarian HGSC, the most prevalent and lethal histologic subtype of epithelial ovarian cancer (EOC). The majority of TP53 mutations are missense mutations, leading to [...] Read more.

Mutations in tumor suppressor gene TP53, encoding for the p53 protein, are the most ubiquitous genetic variation in human ovarian HGSC, the most prevalent and lethal histologic subtype of epithelial ovarian cancer (EOC). The majority of TP53 mutations are missense mutations, leading to loss of tumor suppressive function of p53 and gain of new oncogenic functions. This review presents the clinical relevance of TP53 mutations in HGSC, elaborating on several recently identified upstream regulators of mutant p53 that control its expression and downstream target genes that mediate its roles in the disease. TP53 mutations are the earliest genetic alterations during HGSC pathogenesis, and we summarize current information related to p53 function in the pathogenesis of HGSC. The role of p53 is cell autonomous, and in the interaction between cancer cells and its microenvironment. We discuss the reduction in p53 expression levels in tumor associated fibroblasts that promotes cancer progression, and the role of mutated p53 in the interaction between the tumor and its microenvironment. Lastly, we discuss the potential of TP53 mutations to serve as diagnostic biomarkers and detail some more advanced efforts to use mutated p53 as a therapeutic target in HGSC. Full article

(This article belongs to the Special Issue High-Grade Serous Ovarian Cancer)

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