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Preclinical and Clinical Advances in Ovarian Cancer
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Preclinical and Clinical Advances in Ovarian Cancer

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (30 April 2020) | Viewed by 121286

Special Issue Editor

Dr. Carlos M. Telleria

E-Mail Website
Guest Editor
Experimental Pathology Unit, Department of Pathology, McGill University, Montreal, QC H3A 2B4, Canada
Interests: ovarian cancer; drug repurposing; ovarian cancer development; immunogenic cell death; ER stress
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Ovarian cancer is a major public health concern and remains the deadliest form of gynecological malignancy. Despite survival rates for a number of solid tumors having improved significantly in the last 50 years, the five-year overall survival rate for ovarian cancer has remained stagnant at around 45–47% since the introduction of platinum–taxane chemotherapy following debulking surgery. Whilst in many areas, ovarian cancer continues to elude our understanding, the recent pace of discovery presages a welcome change in overall survival for individuals who will suffer from this disease in the near future.

This Special Issue anticipates an expansion in preclinical and clinical advances in the field. Topics include advances in epidemiology, risk factors, early symptomatology, diagnosis and staging, disease prognosis, prevention, early screening methods, pathobiology of disease initiation and dissemination, biomarkers of disease progression and recurrence, histopathological heterogeneity, genetic expression profiling and molecular subtypes, new surgical strategies, adjuvant therapies, relapse and treatment resistance, and targeted therapies. In particular, this Special Issue will highlight new preclinical models of disease progression, new cell lines and animal models representing the disease, new drugs that show promise for treating ovarian cancer in preclinical studies, and new clinical trials and strategies that contribute to a better quality of life for ovarian cancer patients.

Prof. Carlos M. Telleria
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • ovarian cancer
  • diagnosis
  • biomarkers
  • new drugs
  • clinical trials
  • targeted therapy
  • pathobiology of the disease

Published Papers (27 papers)

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20 pages, 3642 KiB  
Article
Modulation of Immune Infiltration of Ovarian Cancer Tumor Microenvironment by Specific Subpopulations of Fibroblasts
by Ji Wang, Frank H. C. Cheng, Jessica Tedrow, Wennan Chang, Chi Zhang and Anirban K. Mitra
Cancers 2020, 12(11), 3184; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12113184 - 29 Oct 2020
Cited by 12 | Viewed by 3190
Abstract
Tumor immune infiltration plays a key role in the progression of solid tumors, including ovarian cancer, and immunotherapies are rapidly emerging as effective treatment modalities. However, the role of cancer-associated fibroblasts (CAFs), a predominant stromal constituent, in determining the tumor-immune microenvironment and modulating [...] Read more.
Tumor immune infiltration plays a key role in the progression of solid tumors, including ovarian cancer, and immunotherapies are rapidly emerging as effective treatment modalities. However, the role of cancer-associated fibroblasts (CAFs), a predominant stromal constituent, in determining the tumor-immune microenvironment and modulating efficacy of immunotherapies remains poorly understood. We have conducted an extensive bioinformatic analysis of our and other publicly available ovarian cancer datasets (GSE137237, GSE132289 and GSE71340), to determine the correlation of fibroblast subtypes within the tumor microenvironment (TME) with the characteristics of tumor-immune infiltration. We identified (1) four functional modules of CAFs in ovarian cancer that are associated with the TME and metastasis of ovarian cancer, (2) immune-suppressive function of the collagen 1,3,5-expressing CAFs in primary ovarian cancer and omental metastases, and (3) consistent positive correlations between the functional modules of CAFs with anti-immune response genes and negative correlation with pro-immune response genes. Our study identifies a specific fibroblast subtype, fibroblast functional module (FFM)2, in the ovarian cancer tumor microenvironment that can potentially modulate a tumor-promoting immune microenvironment, which may be detrimental toward the effectiveness of ovarian cancer immunotherapies. Full article
(This article belongs to the Special Issue Preclinical and Clinical Advances in Ovarian Cancer)
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26 pages, 4118 KiB  
Article
Modeling the Diversity of Epithelial Ovarian Cancer through Ten Novel Well Characterized Cell Lines Covering Multiple Subtypes of the Disease
by Alexandre Sauriol, Kayla Simeone, Lise Portelance, Liliane Meunier, Kim Leclerc-Desaulniers, Manon de Ladurantaye, Meriem Chergui, Jennifer Kendall-Dupont, Kurosh Rahimi, Euridice Carmona, Diane M. Provencher and Anne-Marie Mes-Masson
Cancers 2020, 12(8), 2222; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12082222 - 08 Aug 2020
Cited by 11 | Viewed by 3110
Abstract
Cancer cell lines are amongst the most important pre-clinical models. In the context of epithelial ovarian cancer, a highly heterogeneous disease with diverse subtypes, it is paramount to study a wide panel of models in order to draw a representative picture of the [...] Read more.
Cancer cell lines are amongst the most important pre-clinical models. In the context of epithelial ovarian cancer, a highly heterogeneous disease with diverse subtypes, it is paramount to study a wide panel of models in order to draw a representative picture of the disease. As this lethal gynaecological malignancy has seen little improvement in overall survival in the last decade, it is all the more pressing to support future research with robust and diverse study models. Here, we describe ten novel spontaneously immortalized patient-derived ovarian cancer cell lines, detailing their respective mutational profiles and gene/biomarker expression patterns, as well as their in vitro and in vivo growth characteristics. Eight of the cell lines were classified as high-grade serous, while two were determined to be of the rarer mucinous and clear cell subtypes, respectively. Each of the ten cell lines presents a panel of characteristics reflective of diverse clinically relevant phenomena, including chemotherapeutic resistance, metastatic potential, and subtype-associated mutations and gene/protein expression profiles. Importantly, four cell lines formed subcutaneous tumors in mice, a key characteristic for pre-clinical drug testing. Our work thus contributes significantly to the available models for the study of ovarian cancer, supplying additional tools to better understand this complex disease. Full article
(This article belongs to the Special Issue Preclinical and Clinical Advances in Ovarian Cancer)
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17 pages, 2571 KiB  
Article
Characterisation of Ovarian Cancer Cell Line NIH-OVCAR3 and Implications of Genomic, Transcriptomic, Proteomic and Functional DNA Damage Response Biomarkers for Therapeutic Targeting
by Alice Bradbury, Rachel O’Donnell, Yvette Drew, Nicola J. Curtin and Sweta Sharma Saha
Cancers 2020, 12(7), 1939; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12071939 - 17 Jul 2020
Cited by 17 | Viewed by 4781
Abstract
In order to be effective models to identify biomarkers of chemotherapy response, cancer cell lines require thorough characterization. In this study, we characterised the widely used high grade serous ovarian cancer (HGSOC) cell line NIH-OVCAR3 using bioinformatics, cytotoxicity assays and molecular/functional analyses of [...] Read more.
In order to be effective models to identify biomarkers of chemotherapy response, cancer cell lines require thorough characterization. In this study, we characterised the widely used high grade serous ovarian cancer (HGSOC) cell line NIH-OVCAR3 using bioinformatics, cytotoxicity assays and molecular/functional analyses of DNA damage response (DDR) pathways in comparison to an ovarian cancer cell line panel. Bioinformatic analysis confirmed the HGSOC-like features of NIH-OVCAR3, including low mutation frequency, TP53 loss and high copy number alteration frequency similar to 201 HGSOCs analysed (TCGA). Cytotoxicity assays were performed for the standard of care chemotherapy, carboplatin, and DDR targeting drugs: rucaparib (a PARP inhibitor) and VE-821 (an ATR inhibitor). Interestingly, NIH-OVCAR3 cells showed sensitivity to carboplatin and rucaparib which was explained by functional loss of homologous recombination repair (HRR) identified by plasmid re-joining assay, despite the ability to form RAD51 foci and absence of mutations in HRR genes. NIH-OVCAR3 cells also showed high non-homologous end joining activity, which may contribute to HRR loss and along with genomic amplification in ATR and TOPBP1, could explain the resistance to VE-821. In summary, NIH-OVCAR3 cells highlight the complexity of HGSOCs and that genomic or functional characterization alone might not be enough to predict/explain chemotherapy response. Full article
(This article belongs to the Special Issue Preclinical and Clinical Advances in Ovarian Cancer)
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16 pages, 72162 KiB  
Article
Novel Molecular Targets for Tumor-Specific Imaging of Epithelial Ovarian Cancer Metastases
by Lysanne D. A. N. de Muynck, Katja N. Gaarenstroom, Cornelis F. M. Sier, Maurice van Duijvenvoorde, Tjalling Bosse, J. Sven D. Mieog, Cornelis D. de Kroon, Alexander L. Vahrmeijer and Inge T. A. Peters
Cancers 2020, 12(6), 1562; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12061562 - 12 Jun 2020
Cited by 9 | Viewed by 3109
Abstract
In epithelial ovarian cancer (EOC), the strongest prognostic factor is the completeness of surgery. Intraoperative molecular imaging that targets cell-surface proteins on tumor cells may guide surgeons to detect metastases otherwise not visible to the naked eye. Previously, we identified 29% more metastatic [...] Read more.
In epithelial ovarian cancer (EOC), the strongest prognostic factor is the completeness of surgery. Intraoperative molecular imaging that targets cell-surface proteins on tumor cells may guide surgeons to detect metastases otherwise not visible to the naked eye. Previously, we identified 29% more metastatic lesions during cytoreductive surgery using OTL-38, a fluorescent tracer targeting folate receptor-α (FRα). Unfortunately, eleven out of thirteen fluorescent lymph nodes were tumor negative. The current study evaluates the suitability of five biomarkers (EGFR, VEGF-A, L1CAM, integrin αvβ6 and EpCAM) as alternative targets for molecular imaging of EOC metastases and included FRα as a reference. Immunohistochemistry was performed on paraffin-embedded tissue sections of primary ovarian tumors, omental, peritoneal and lymph node metastases from 84 EOC patients. Tumor-negative tissue specimens from these patients were included as controls. EGFR, VEGF-A and L1CAM were highly expressed in tumor-negative tissue, whereas αvβ6 showed heterogeneous expression in metastases. The expression of EpCAM was most comparable to FRα in metastatic lesions and completely absent in the lymph nodes that were false-positively illuminated with OTL-38 in our previous study. Hence, EpCAM seems to be a promising novel target for intraoperative imaging and may contribute to a more reliable detection of true metastatic EOC lesions. Full article
(This article belongs to the Special Issue Preclinical and Clinical Advances in Ovarian Cancer)
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15 pages, 3904 KiB  
Article
Compressive Stimulation Enhances Ovarian Cancer Proliferation, Invasion, Chemoresistance, and Mechanotransduction via CDC42 in a 3D Bioreactor
by Caymen M. Novak, Eric N. Horst, Emily Lin and Geeta Mehta
Cancers 2020, 12(6), 1521; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12061521 - 10 Jun 2020
Cited by 29 | Viewed by 3753
Abstract
This report investigates the role of compressive stress on ovarian cancer in a 3D custom built bioreactor. Cells within the ovarian tumor microenvironment experience a range of compressive stimuli that contribute to mechanotransduction. As the ovarian tumor expands, cells are exposed to chronic [...] Read more.
This report investigates the role of compressive stress on ovarian cancer in a 3D custom built bioreactor. Cells within the ovarian tumor microenvironment experience a range of compressive stimuli that contribute to mechanotransduction. As the ovarian tumor expands, cells are exposed to chronic load from hydrostatic pressure, displacement of surrounding cells, and growth induced stress. External dynamic stimuli have been correlated with an increase in metastasis, cancer stem cell marker expression, chemoresistance, and proliferation in a variety of cancers. However, how these compressive stimuli contribute to ovarian cancer progression is not fully understood. In this report, high grade serous ovarian cancer cell lines were encapsulated within an ECM mimicking hydrogel comprising of agarose and collagen type I, and stimulated with confined cyclic or static compressive stresses for 24 and 72 h. Compression stimulation resulted in a significant increase in proliferation, invasive morphology, and chemoresistance. Additionally, CDC42 was upregulated in compression stimulated conditions, and was necessary to drive increased proliferation and chemoresistance. Inhibition of CDC42 lead to significant decrease in proliferation, survival, and increased chemosensitivity. In summary, the dynamic in vitro 3D platform developed in this report, is ideal for understanding the influence of compressive stimuli, and can be widely applicable to any epithelial cancers. This work reinforces the critical need to consider compressive stimulation in basic cancer biology and therapeutic developments. Full article
(This article belongs to the Special Issue Preclinical and Clinical Advances in Ovarian Cancer)
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14 pages, 2126 KiB  
Article
Identifying and Overcoming Mechanisms of PARP Inhibitor Resistance in Homologous Recombination Repair-Deficient and Repair-Proficient High Grade Serous Ovarian Cancer Cells
by Miriam K. Gomez, Giuditta Illuzzi, Carlota Colomer, Michael Churchman, Robert L. Hollis, Mark J. O’Connor, Charlie Gourley, Elisabetta Leo and David W. Melton
Cancers 2020, 12(6), 1503; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12061503 - 09 Jun 2020
Cited by 17 | Viewed by 4131
Abstract
High grade serous ovarian cancer (HGSOC) is a major cause of female cancer mortality. The approval of poly (ADP-ribose) polymerase (PARP) inhibitors for clinical use has greatly improved treatment options for patients with homologous recombination repair (HRR)-deficient HGSOC, although the development of PARP [...] Read more.
High grade serous ovarian cancer (HGSOC) is a major cause of female cancer mortality. The approval of poly (ADP-ribose) polymerase (PARP) inhibitors for clinical use has greatly improved treatment options for patients with homologous recombination repair (HRR)-deficient HGSOC, although the development of PARP inhibitor resistance in some patients is revealing limitations to outcome. A proportion of patients with HRR-proficient cancers also benefit from PARP inhibitor therapy. Our aim is to compare mechanisms of resistance to the PARP inhibitor olaparib in these two main molecular categories of HGSOC and investigate a way to overcome resistance that we considered particularly suited to a cancer like HGSOC, where there is a very high incidence of TP53 gene mutation, making HGSOC cells heavily reliant on the G2 checkpoint for repair of DNA damage and survival. We identified alterations in multiple factors involved in resistance to PARP inhibition in both HRR-proficient and -deficient cancers. The most frequent change was a major reduction in levels of poly (ADP-ribose) glycohydrolase (PARG), which would be expected to preserve a residual PARP1-initiated DNA damage response to DNA single-strand breaks. Other changes seen would be expected to boost levels of HRR of DNA double-strand breaks. Growth of all olaparib-resistant clones isolated could be controlled by WEE1 kinase inhibitor AZD1775, which inactivates the G2 checkpoint. Our work suggests that use of the WEE1 kinase inhibitor could be a realistic therapeutic option for patients that develop resistance to olaparib. Full article
(This article belongs to the Special Issue Preclinical and Clinical Advances in Ovarian Cancer)
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25 pages, 3216 KiB  
Article
Azasteroid Alkylators as Dual Inhibitors of AKT and ERK Signaling for the Treatment of Ovarian Carcinoma
by Panagiotis Dalezis, Eleni Geromichalou, Aikaterini Polonifi, Sofia Sagredou, Nikolaos Nikoleousakos, Michael Nikolaou, Vasiliki Sarli, Mihalis I. Panayiotidis and Dimitrios T. Trafalis
Cancers 2020, 12(5), 1263; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12051263 - 16 May 2020
Cited by 4 | Viewed by 2936
Abstract
(1) Background: Previous findings show that lactam steroidal alkylating esters display improved therapeutic efficacy with reduced toxicity. The aim of this study was to evaluate the anticancer activity of two newly synthesized aza-steroid alkylators (ENGA-L06E and ENGA-L08E) against human ovarian carcinoma cells, and [...] Read more.
(1) Background: Previous findings show that lactam steroidal alkylating esters display improved therapeutic efficacy with reduced toxicity. The aim of this study was to evaluate the anticancer activity of two newly synthesized aza-steroid alkylators (ENGA-L06E and ENGA-L08E) against human ovarian carcinoma cells, and consequently, the dual inhibition of RAS/PI3K/AKT and RAS/RAF/MEK/ERK signaling pathways, both of which are closely associated with ovarian cancer; (2) Methods: The in vitro cytostatic and cytotoxic effects of ENGA-L06E and ENGA-L08E were evaluated in a panel of five human ovarian cancer cell lines, as well as in in vivo studies. ENGA-L06E and ENGA-L08E, in addition to another two aniline-mustard alkylators, POPAM and melphalan (L-PAM), were utilized in order to determine the acute toxicity and antitumor efficacy on two human ovarian xenograft models. Also, in silico studies were performed in order to investigate the dual inhibition of ENGA-L06E and ENGA-L08E on RAS/PI3K/AKT and RAS/RAF/MEK/ERK signaling pathways; (3) Results: Both, in vitro and in vivo studies demonstrated that ENGA-L06E and ENGA-L08E were significantly more effective with a lower toxicity profile in comparison to POPAM and L-PAM alkylators. Moreover, in silico studies demonstrated that the two new aza-steroid alkylators could act as efficient inhibitors of the phosphorylation of AKT and ERK1/2 molecules; and (4) Conclusions: Both ENGA-L06E and ENGA-L08E demonstrated high anticancer activity through the inhibition of the PI3K-AKT and KRAS-ERK signaling pathways against human ovarian carcinoma, and thus constituting strong evidence towards further clinical development. Full article
(This article belongs to the Special Issue Preclinical and Clinical Advances in Ovarian Cancer)
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23 pages, 3562 KiB  
Article
A Novel Role for NUAK1 in Promoting Ovarian Cancer Metastasis through Regulation of Fibronectin Production in Spheroids
by Jamie Lee Fritz, Olga Collins, Parima Saxena, Adrian Buensuceso, Yudith Ramos Valdes, Kyle E. Francis, Kevin R. Brown, Brett Larsen, Karen Colwill, Anne-Claude Gingras, Robert Rottapel and Trevor G. Shepherd
Cancers 2020, 12(5), 1250; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12051250 - 15 May 2020
Cited by 20 | Viewed by 6469
Abstract
Epithelial ovarian cancer (EOC) has a unique mode of metastasis, where cells shed from the primary tumour, form aggregates called spheroids to evade anoikis, spread through the peritoneal cavity, and adhere to secondary sites. We previously showed that the master kinase Liver kinase [...] Read more.
Epithelial ovarian cancer (EOC) has a unique mode of metastasis, where cells shed from the primary tumour, form aggregates called spheroids to evade anoikis, spread through the peritoneal cavity, and adhere to secondary sites. We previously showed that the master kinase Liver kinase B1 (LKB1) is required for EOC spheroid viability and metastasis. We have identified novel (nua) kinase 1 (NUAK1) as a top candidate LKB1 substrate in EOC cells and spheroids using a multiplex inhibitor beads-mass spectrometry approach. We confirmed that LKB1 maintains NUAK1 phosphorylation and promotes its stabilization. We next investigated NUAK1 function in EOC cells. Ectopic NUAK1-overexpressing EOC cell lines had increased adhesion, whereas the reverse was seen in OVCAR8-NUAK1KO cells. In fact, cells with NUAK1 loss generate spheroids with reduced integrity, leading to increased cell death after long-term culture. Following transcriptome analysis, we identified reduced enrichment for cell interaction gene expression pathways in OVCAR8-NUAK1KO spheroids. In fact, the FN1 gene, encoding fibronectin, exhibited a 745-fold decreased expression in NUAK1KO spheroids. Fibronectin expression was induced during native spheroid formation, yet this was completely lost in NUAK1KO spheroids. Co-incubation with soluble fibronectin restored the compact spheroid phenotype to OVCAR8-NUAK1KO cells. In a xenograft model of intraperitoneal metastasis, NUAK1 loss extended survival and reduced fibronectin expression in tumours. Thus, we have identified a new mechanism controlling EOC metastasis, through which LKB1-NUAK1 activity promotes spheroid formation and secondary tumours via fibronectin production. Full article
(This article belongs to the Special Issue Preclinical and Clinical Advances in Ovarian Cancer)
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21 pages, 3047 KiB  
Article
The Extracellular Matrix Influences Ovarian Carcinoma Cells’ Sensitivity to Cisplatinum: A First Step towards Personalized Medicine
by Andrea Balduit, Chiara Agostinis, Alessandro Mangogna, Veronica Maggi, Gabriella Zito, Federico Romano, Andrea Romano, Rita Ceccherini, Gabriele Grassi, Serena Bonin, Deborah Bonazza, Fabrizio Zanconati, Giuseppe Ricci and Roberta Bulla
Cancers 2020, 12(5), 1175; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12051175 - 07 May 2020
Cited by 10 | Viewed by 3695
Abstract
The development of personalized therapies for ovarian carcinoma patients is still hampered by several limitations, mainly the difficulty of predicting patients’ responses to chemotherapy in tumor cells isolated from peritoneal fluids. The main reason for the low predictive power of in vitro assays [...] Read more.
The development of personalized therapies for ovarian carcinoma patients is still hampered by several limitations, mainly the difficulty of predicting patients’ responses to chemotherapy in tumor cells isolated from peritoneal fluids. The main reason for the low predictive power of in vitro assays is related to the modification of the cancer cells’ phenotype induced by the culture conditions, which results in changes to the activation state and drug sensitivity of tumor cells compared to their in vivo properties. We have defined the optimal culture conditions to set up a prognostic test to predict high-grade serous ovarian carcinoma (HGSOC) patients’ responses to platinum chemotherapy. We evaluated the effects of hyaluronic acid (HA) and fibronectin matrices and the contribution of freezing/thawing processes to the cell response to platinum-based treatment, collecting spheroids from the ascitic fluids of 13 patients with stage II or III HGSOC. Our findings indicated that an efficient model used to generate predictive data for in vivo sensitivity to platinum is culturing fresh spheroids on HA, avoiding the use of previously frozen primary tumor cells. The establishment of this easy, reproducible and standardized testing method can significantly contribute to an improvement in therapeutic effectiveness, thus bringing the prospect of personalized therapy closer for ovarian carcinoma patients. Full article
(This article belongs to the Special Issue Preclinical and Clinical Advances in Ovarian Cancer)
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16 pages, 5547 KiB  
Article
Integrative Transcriptome Analyses of the Human Fallopian Tube: Fimbria and Ampulla—Site of Origin of Serous Carcinoma of the Ovary
by Ramlogan Sowamber, Omar Nelson, Leah Dodds, Victoria DeCastro, Iru Paudel, Anca Milea, Michael Considine, Leslie Cope, Andre Pinto, Matthew Schlumbrecht, Brian Slomovitz, Patricia A. Shaw and Sophia H. L. George
Cancers 2020, 12(5), 1090; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12051090 - 27 Apr 2020
Cited by 10 | Viewed by 4097
Abstract
Epithelial ovarian cancer represents a group of heterogeneous diseases with high grade serous cancer (HGSC) representing the most common histotype. Molecular profiles of precancerous lesions found in the fallopian tube have implicated this tissue as the presumptive site of origin of HGSC. Precancerous [...] Read more.
Epithelial ovarian cancer represents a group of heterogeneous diseases with high grade serous cancer (HGSC) representing the most common histotype. Molecular profiles of precancerous lesions found in the fallopian tube have implicated this tissue as the presumptive site of origin of HGSC. Precancerous lesions are primarily found in the distal fallopian tube (fimbria), near the ovary relative to the proximal tissue (ampulla), nearer to the uterus. The proximity of the fimbria to the ovary and the link between ovulation, through follicular fluid release, and ovarian cancer risk led us to examine transcriptional responses of fallopian tube epithelia (FTE) at the different anatomical sites of the human fallopian tube. Gene expression profiles of matched FTE from the fimbria and from premenopausal women resulted in differentially expressed genes (DEGs): CYYR1, SALL1, FOXP2, TAAR1, AKR1C2/C3/C4, NMBR, ME1 and GSTA2. These genes are part of the antioxidant, stem and inflammation pathways. Comparisons between the luteal phase (post-ovulation) to the follicular phase (pre-ovulation) demonstrated greater differences in DEGs than a comparison between fimbria and fallopian tube anatomical differences alone. This data suggests that cyclical transcriptional changes experienced in pre-menopause are inherent physiological triggers that expose the FTE in the fimbria to cytotoxic stressors. These cyclical exposures induce transcriptional changes reflective of genotoxic and cytotoxic damage to the FTE in the fimbria which are closely related to transcriptional and genomic alterations observed in ovarian cancer. Full article
(This article belongs to the Special Issue Preclinical and Clinical Advances in Ovarian Cancer)
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19 pages, 1908 KiB  
Article
Clinical Value of lncRNA MEG3 in High-Grade Serous Ovarian Cancer
by Marianna Buttarelli, Marta De Donato, Giuseppina Raspaglio, Gabriele Babini, Alessandra Ciucci, Enrica Martinelli, Pina Baccaro, Tina Pasciuto, Anna Fagotti, Giovanni Scambia and Daniela Gallo
Cancers 2020, 12(4), 966; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12040966 - 14 Apr 2020
Cited by 24 | Viewed by 10622
Abstract
Long non-coding RNAs (lncRNAs) are emerging as regulators in cancer development and progression, and aberrant lncRNA profiles have been reported in several cancers. Here, we evaluated the potential of using the maternally expressed gene 3 (MEG3) tissue level as a prognostic marker in [...] Read more.
Long non-coding RNAs (lncRNAs) are emerging as regulators in cancer development and progression, and aberrant lncRNA profiles have been reported in several cancers. Here, we evaluated the potential of using the maternally expressed gene 3 (MEG3) tissue level as a prognostic marker in high-grade serous ovarian cancer (HGSOC), the most common and deadliest gynecologic malignancy. To the aim of the study, we measured MEG3 transcript levels in 90 pre-treatment peritoneal biopsies. We also investigated MEG3 function in ovarian cancer biology. We found that high MEG3 expression was independently associated with better progression-free (p = 0.002) and overall survival (p = 0.01). In vitro and in vivo preclinical studies supported a role for MEG3 as a tumor suppressor in HGSOC, possibly through modulation of the phosphatase and tensin homologue (PTEN) network. Overall, results from this study demonstrated that decreased MEG3 is a hallmark for malignancy and tumor progression in HGSOC. Full article
(This article belongs to the Special Issue Preclinical and Clinical Advances in Ovarian Cancer)
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14 pages, 862 KiB  
Article
30 Years of Experience in the Management of Stage III and IV Epithelial Ovarian Cancer: Impact of Surgical Strategies on Survival
by Berenice Delga, Jean-Marc Classe, Gilles Houvenaeghel, Guillaume Blache, Laura Sabiani, Houssein El Hajj, Nicole Andrieux and Eric Lambaudie
Cancers 2020, 12(3), 768; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12030768 - 24 Mar 2020
Cited by 19 | Viewed by 3354
Abstract
Objective: to analyze the evolution of surgical techniques and strategies, and to determine their influence on the survival of patients with stage III or IV epithelial ovarian cancer (EOC). Methods: a retrospective data analysis was performed in two French tertiary cancer [...] Read more.
Objective: to analyze the evolution of surgical techniques and strategies, and to determine their influence on the survival of patients with stage III or IV epithelial ovarian cancer (EOC). Methods: a retrospective data analysis was performed in two French tertiary cancer institutes. The analysis included clinical information, cytoreductive outcome (complete, optimal and suboptimal), definitive pathology, Overall Survival (OS), and Progression-Free Survival (PFS). Three surgical strategies were compared: Primary Cytoreductive Surgery (PCS), Interval Cytoreductive Surgery (ICS) after three cycles of Neo-Adjuvant Chemotherapy (NAC), and Final Cytoreductive Surgery (FCS) after at least six cycles of NAC. We analyzed four distinct time intervals: prior to 2000, between 2000 and 2004, between 2005 and 2009, and after 2009. Results: data from 1474 patients managed for International Federation of Gynecology and Obstetrics (FIGO) stages III (80%) or IV (20%) EOC were analyzed. Throughout the four time intervals, the rate of patients who were treated only medically increased significantly (10.1% vs. 22.6% p < 0.001). NAC treatment increased from 20.1% to 52.2% (p < 0.001). Complete resection rate increased from 37% to 66.2% (p < 0.001). Of our study population, 1260 patients (85.5%) underwent surgery. OS was longer in cases of complete cytoreduction (Hazard Ratio (HR) = 2.123 CI 95% [1.816–2.481] p < 0.001) but the surgical strategy itself did not affect median OS. OS was 44.9 months, 50.3 months, and 42 months for PCS, ICS, and FCS, respectively (p = 0.410). After adjusting for surgical strategies (PCS, ICS, and FCS), all patients with complete cytoreduction presented similar OS with no significant difference. However, PFS was three months shorter when FCS was compared to PCS (p < 0.001). Conclusion: In our 30 years’ experience of EOC management, complete resection rate was the only independent factor that significantly improved OS and PFS, regardless of the surgical strategy. Full article
(This article belongs to the Special Issue Preclinical and Clinical Advances in Ovarian Cancer)
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26 pages, 6731 KiB  
Article
The Capacity of High-Grade Serous Ovarian Cancer Cells to Form Multicellular Structures Spontaneously along Disease Progression Correlates with Their Orthotopic Tumorigenicity in Immunosuppressed Mice
by Alicia Goyeneche, Michael-Anthony Lisio, Lili Fu, Rekha Srinivasan, Juan Valdez Capuccino, Zu-hua Gao and Carlos Telleria
Cancers 2020, 12(3), 699; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12030699 - 16 Mar 2020
Cited by 10 | Viewed by 3077
Abstract
Many studies have examined the biology, genetics, and chemotherapeutic response of ovarian cancer’s solid component; its liquid facet, however, remains critically underinvestigated. Floating within peritoneal effusions known as ascites, ovarian cancer cells form multicellular structures, creating a cancer niche in suspension. This study [...] Read more.
Many studies have examined the biology, genetics, and chemotherapeutic response of ovarian cancer’s solid component; its liquid facet, however, remains critically underinvestigated. Floating within peritoneal effusions known as ascites, ovarian cancer cells form multicellular structures, creating a cancer niche in suspension. This study explores the pathobiology of spontaneously formed, multicellular, ovarian cancer structures derived from serous ovarian cancer cells isolated along disease evolution. It also tests their capacity to cause peritoneal disease in immunosuppressed mice. Results stem from an analysis of cell lines representing the most frequently diagnosed ovarian cancer histotype (high-grade serous ovarian cancer), derived from ascites of the same patient at distinct stages of disease progression. When cultured under adherent conditions, in addition to forming cellular monolayers, the cultures developed areas in which the cells grew upwards, forming densely packed multilayers that ultimately detached from the bottom of the plates and lived as free-floating, multicellular structures. The capacity to form foci and to develop multicellular structures was proportional to disease progression at the time of ascites extraction. Self-assembled in culture, these structures varied in size, were either compact or hollow, irregular, or spheroidal, and exhibited replicative capacity and an epithelial nature. Furthermore, they fully recreated ovarian cancer disease in immunosuppressed mice: accumulation of malignant ascites and pleural effusions; formation of discrete, solid, macroscopic, peritoneal tumors; and microscopic growths in abdominal organs. They also reproduced the histopathological features characteristic of high-grade serous ovarian cancer when diagnosed in patients. The following results encourage the development of therapeutic interventions to interrupt the formation and/or survival of multicellular structures that constitute a floating niche in the peritoneal fluid, which in turn halts disease progression and prevents recurrence. Full article
(This article belongs to the Special Issue Preclinical and Clinical Advances in Ovarian Cancer)
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12 pages, 2053 KiB  
Article
RNA Immune Signatures from Pan-Cancer Analysis Are Prognostic for High-Grade Serous Ovarian Cancer and Other Female Cancers
by Wendell D. Jones, Chad M. Michener, Charles Biscotti, Iona Braicu, Jalid Sehouli, Mahrukh K. Ganapathi and Ram N. Ganapathi
Cancers 2020, 12(3), 620; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12030620 - 07 Mar 2020
Cited by 13 | Viewed by 4568
Abstract
Immune cell infiltrates within the tumor microenvironment can influence treatment response and outcome in several cancers. In this study, we developed RNA-based immune signatures from pan-cancer analysis that could serve as potential markers across tumor types and tested them for association with outcome [...] Read more.
Immune cell infiltrates within the tumor microenvironment can influence treatment response and outcome in several cancers. In this study, we developed RNA-based immune signatures from pan-cancer analysis that could serve as potential markers across tumor types and tested them for association with outcome in high-grade serous ovarian cancer (HGSOC) and other female cancers. Pan-cancer RNA-Seq cluster analysis of immune-related gene expression profiles in The Cancer Genome Atlas (TCGA) from 29 different solid tumors (4446 specimens) identified distinct but concordant gene signatures. Among these immune signatures, Cytotoxic Lymphocyte Immune Signature (CLIS), T-cell trafficking (TCT), and the TCT to M2 tumor-associated macrophage (M2TAM) ratio (TCT:M2TAM) were significantly (p < 0.05) associated with overall survival (OS), using multivariable Cox proportional hazards regression models, in a discovery cohort and two independent validation cohorts of HGSOC patients. Notably, the TCT:M2TAM ratio was highly significant (p ≤ 0.000001) in two HGSOC cohorts. Immune signatures were also significant (p < 0.05) in the presence of tumor cytoreduction, BRCA1/2 mutation, and COL2A1 expression. Importantly, the CLIS and TCT signatures were also validated for prognostic significance (p < 0.05) in TCGA cohorts for endometrial and high tumor mutational burden (Hi-TMB) breast cancer. These immune signatures also have the potential for being predictive in other cancers and for patients following different treatment strategies. Full article
(This article belongs to the Special Issue Preclinical and Clinical Advances in Ovarian Cancer)
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13 pages, 1165 KiB  
Article
Precision Medicine Tumor Boards: Clinical Applicability of Personalized Treatment Concepts in Ovarian Cancer
by Stefanie Aust, Richard Schwameis, Tamara Gagic, Leonhard Müllauer, Eva Langthaler, Gerald Prager, Christina Grech, Alexander Reinthaller, Michael Krainer, Dietmar Pils, Christoph Grimm and Stephan Polterauer
Cancers 2020, 12(3), 548; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12030548 - 27 Feb 2020
Cited by 13 | Viewed by 3262
Abstract
Background: Treating cancer according to its molecular alterations (i.e., targeted treatment, TT) is the goal of precision medicine tumor boards (PTBs). Their clinical applicability has been evaluated for ovarian cancer patients in this analysis. Methods: All consecutive ovarian cancer patients discussed in a [...] Read more.
Background: Treating cancer according to its molecular alterations (i.e., targeted treatment, TT) is the goal of precision medicine tumor boards (PTBs). Their clinical applicability has been evaluated for ovarian cancer patients in this analysis. Methods: All consecutive ovarian cancer patients discussed in a PTB at the Medical University of Vienna, Austria, from April 2015 to April 2019 were included (n = 44). Results: In 38/44 (86%) cases, at least one mutation, deletion or amplification was detected. The most frequently altered genes were p53 (64%), PI3K pathway (18%), KRAS (14%), BRCA1 (11%) and BRCA2 (2%). In 31 patients (70%) a TT was recommended. A total of 12/31 patients (39%) received the recommended therapy. Median time from indication for PTB to TT start was 65 days (15–216). Median time to treatment failure was 2.7 months (0.2–13.2). Clinical benefit rate (CBR) was 42%. Reasons for treatment discontinuation were disease progression (42%), poor performance status (PS > 2; 25%), death (17%) or treatment related side effects (8%). In 61% the TT was not administered—mainly due to PS > 2. Conclusion: Even though a TT recommendation can be derived frequently, clinical applicability remains limited due to poor patients’ general condition after exploitation of standard treatment. However, we observed antitumor activity in a substantial number of heavily pretreated patients. Full article
(This article belongs to the Special Issue Preclinical and Clinical Advances in Ovarian Cancer)
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21 pages, 2768 KiB  
Article
Metabolism of Estrogens: Turnover Differs between Platinum-Sensitive and -Resistant High-Grade Serous Ovarian Cancer Cells
by Stefan Poschner, Judith Wackerlig, Dan Cacsire Castillo-Tong, Andrea Wolf, Isabel von der Decken, Tea Lanišnik Rižner, Renata Pavlič, Anastasia Meshcheryakova, Diana Mechtcheriakova, Monika Fritzer-Szekeres, Theresia Thalhammer and Walter Jäger
Cancers 2020, 12(2), 279; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12020279 - 23 Jan 2020
Cited by 6 | Viewed by 3480
Abstract
High-grade serous ovarian cancer (HGSOC) is currently treated with cytoreductive surgery and platinum-based chemotherapy. The majority of patients show a primary response; however, many rapidly develop drug resistance. Antiestrogens have been studied as low toxic treatment options for HGSOC, with higher response rates [...] Read more.
High-grade serous ovarian cancer (HGSOC) is currently treated with cytoreductive surgery and platinum-based chemotherapy. The majority of patients show a primary response; however, many rapidly develop drug resistance. Antiestrogens have been studied as low toxic treatment options for HGSOC, with higher response rates in platinum-sensitive cases. Mechanisms for this difference in response remain unknown. Therefore, the present study investigated the impact of platinum resistance on steroid metabolism in six established HGSOC cell lines sensitive and resistant against carboplatin using a high-resolution mass spectrometry assay to simultaneously quantify the ten main steroids of the estrogenic metabolic pathway. An up to 60-fold higher formation of steroid hormones and their sulfated or glucuronidated metabolites was observed in carboplatin-sensitive cells, which was reversible by treatment with interleukin-6 (IL-6). Conversely, treatment of carboplatin-resistant cells expressing high levels of endogenous IL-6 with the monoclonal anti-IL-6R antibody tocilizumab changed their status to “platinum-sensitive”, exhibiting a decreased IC50 value for carboplatin, decreased growth, and significantly higher estrogen metabolism. Analysis of these metabolic differences could help to detect platinum resistance in HGSOC patients earlier, thereby allowing more efficient interventions. Full article
(This article belongs to the Special Issue Preclinical and Clinical Advances in Ovarian Cancer)
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14 pages, 1388 KiB  
Article
Relative Ratios Enhance the Diagnostic Power of Phospholipids in Distinguishing Benign and Cancerous Ovarian Masses
by Tsukasa Yagi, Cyrus E. Kuschner, Muhammad Shoaib, Rishabh C. Choudhary, Lance B. Becker, Annette T. Lee and Junhwan Kim
Cancers 2020, 12(1), 72; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12010072 - 26 Dec 2019
Cited by 7 | Viewed by 3001
Abstract
Ovarian cancer remains a highly lethal disease due to its late clinical presentation and lack of reliable early biomarkers. Protein-based diagnostic markers have presented limitations in identifying ovarian cancer. We tested the potential of phospholipids as markers of ovarian cancer by utilizing inter-related [...] Read more.
Ovarian cancer remains a highly lethal disease due to its late clinical presentation and lack of reliable early biomarkers. Protein-based diagnostic markers have presented limitations in identifying ovarian cancer. We tested the potential of phospholipids as markers of ovarian cancer by utilizing inter-related regulation of phospholipids, a unique property that allows the use of ratios between phospholipid species for quantitation. High-performance liquid chromatography mass spectrometry was used to measure phospholipid, lysophospholipid, and sphingophospholipid content in plasma from patients with benign ovarian masses, patients with ovarian cancer, and controls. We applied both absolute and relative phospholipid ratios for quantitation. Receiver operating characteristic analysis was performed to test the sensitivity and specificity. We found that utilization of ratios between phospholipid species greatly outperformed absolute quantitation in the identification of ovarian cancer. Of the phospholipids analyzed, species in phosphatidylcholine (PC), lysophosphatidylcholine (LPC), and sphingomyelin (SM) were found to have great biomarker potential. LPC(20:4)/LPC(18:0) carried the greatest capacity to differentiate cancer from control, SM(d18:1/24:1)/SM(d18:1/22:0) to differentiate benign from cancer, and PC(18:0/20:4)/PC(18:0/18:1) to differentiate benign from control. These results demonstrate the potential of plasma phospholipids as a novel marker of ovarian cancer by utilizing the unique characteristics of phospholipids to further enhance the diagnostic power. Full article
(This article belongs to the Special Issue Preclinical and Clinical Advances in Ovarian Cancer)
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13 pages, 1060 KiB  
Article
Tumor BRCA Test for Patients with Epithelial Ovarian Cancer: The Role of Molecular Pathology in the Era of PARP Inhibitor Therapy
by Caterina Fumagalli, Federica Tomao, Ilaria Betella, Alessandra Rappa, Mariarosaria Calvello, Bernardo Bonanni, Loris Bernard, Fedro Peccatori, Nicoletta Colombo, Giuseppe Viale, Massimo Barberis and Elena Guerini-Rocco
Cancers 2019, 11(11), 1641; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11111641 - 24 Oct 2019
Cited by 22 | Viewed by 4068
Abstract
The PARP inhibitor olaparib has been approved in the maintenance setting of platinum-sensitive epithelial ovarian cancer patients with germline or somatic BRCA1/2 mutation. Therefore, the availability of a tumor BRCA test has become a clinical need. We report the results of the clinical [...] Read more.
The PARP inhibitor olaparib has been approved in the maintenance setting of platinum-sensitive epithelial ovarian cancer patients with germline or somatic BRCA1/2 mutation. Therefore, the availability of a tumor BRCA test has become a clinical need. We report the results of the clinical implementation of a tumor BRCA test within the frame of an institutional workflow for the management of patients with nonmucinous and nonborderline epithelial ovarian cancer. In total, 223 patients with epithelial ovarian cancer were prospectively analyzed. BRCA1/2 status was evaluated on formalin-fixed, paraffin-embedded tumor specimens using next-generation sequencing technology. The tumor BRCA test had a success rate of 99.1% (221 of 223 successfully analyzed cases) and a median turnaround time of 17 calendar days. Among the 221 cases, BRCA1 or BRCA2 pathogenic/likely pathogenic mutations were found in 62 (28.1%) cases and variants of uncertain significance in 25 (11.3%) cases. The concordance rate between tumor BRCA test results and germline BRCA1/2 status was 87%, with five cases harboring pathogenic/likely pathogenic somatic-only mutations. The next-generation, sequencing-based tumor BRCA test showed a high success rate and a turnaround time compatible with clinical purposes. The tumor BRCA test could be implemented in a molecular diagnostic setting and it may guide the clinical management of patients with epithelial ovarian cancer. Full article
(This article belongs to the Special Issue Preclinical and Clinical Advances in Ovarian Cancer)
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Review

Jump to: Research

24 pages, 299 KiB  
Review
Measuring Quality of Life in Ovarian Cancer Clinical Trials—Can We Improve Objectivity and Cross Trial Comparisons?
by Gita Bhat, Katherine Karakasis and Amit M. Oza
Cancers 2020, 12(11), 3296; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12113296 - 07 Nov 2020
Cited by 11 | Viewed by 2701
Abstract
Epithelial ovarian cancer (EOC) remains a lethal disease for the majority of women diagnosed with it worldwide. For the majority of patients, diagnosis occurs late, in the advanced setting. Disease-induced as well as treatment-related adverse events can negatively impact quality of life (QoL). [...] Read more.
Epithelial ovarian cancer (EOC) remains a lethal disease for the majority of women diagnosed with it worldwide. For the majority of patients, diagnosis occurs late, in the advanced setting. Disease-induced as well as treatment-related adverse events can negatively impact quality of life (QoL). Research to date has captured these data through use of patient-related outcomes (PROs) and, increasingly, has become an area of increased attention and focus in clinical trial reporting. QoL/PRO measurements in EOC clinical trials at different transition points in a patient’s journey are increasingly being recognized by patients, clinicians and regulatory agencies as the key determinants of treatment benefit. Various context-specific PROs and PRO endpoints have been described for clinical trials in EOC. Standardized approaches and checklists for incorporating PRO endpoints in clinical trials have been proposed. In a real-world clinical practice setting, PRO/QoL measures, which are meaningful, valid, reliable, feasible and acceptable to patients and clinicians, need to be implemented and used. These may assist by serving as screening tools; helping with the identification of patient preferences to aid in decision making; improving patient–provider communication; facilitating shared decision making. Importantly, they may also improve quality of care through an increasingly patient-centered approach. Potential areas of future research include assessment of anxiety, depression and other mental health issues. In good prognostic groups, such as maintenance clinical trials, following patients beyond progression will capture possible downstream effects related to delaying the psychological trauma of relapse, symptoms due to disease progression and side-effects of subsequent chemotherapy. Identifying PRO endpoints in next-generation-targeted therapies (including immunotherapies) also warrants investigation. Full article
(This article belongs to the Special Issue Preclinical and Clinical Advances in Ovarian Cancer)
18 pages, 592 KiB  
Review
Front-Line Maintenance Therapy in Advanced Ovarian Cancer—Current Advances and Perspectives
by Thibaut Reverdy, Christophe Sajous, Julien Péron, Olivier Glehen, Naoual Bakrin, Witold Gertych, Jonathan Lopez, Benoit You and Gilles Freyer
Cancers 2020, 12(9), 2414; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12092414 - 25 Aug 2020
Cited by 9 | Viewed by 3314
Abstract
Ovarian tumor is the gynecological cancer associated with the highest mortality. Most diseases are diagnosed at an advanced stage, which impairs the chances of prolonged complete remission. The standard front-line treatment of advanced stages combines surgery in an expert center with platinum-based chemotherapy. [...] Read more.
Ovarian tumor is the gynecological cancer associated with the highest mortality. Most diseases are diagnosed at an advanced stage, which impairs the chances of prolonged complete remission. The standard front-line treatment of advanced stages combines surgery in an expert center with platinum-based chemotherapy. Most patients experience a relapse in the years following the initial treatment. During the last decade, anti-angiogenic agents used in the maintenance setting improved progression free survival (PFS) over chemotherapy alone. More recently, PARP inhibitors demonstrated substantial efficacy, mainly in patients with germinal or somatic BRCA mutations or other homologous recombination deficiencies (HRD), all involved in double strand DNA Damage Repair (DDR). Other therapeutic paradigms are currently being explored, including combinations of immune-checkpoints inhibitors, chemotherapy, bevacizumab and PARP inhibitors. In addition to these clinical advances, molecular characterization of the tumors and their correlations with drugs efficacy are needed to better understand which patient will benefit the most from the various treatments available to date. Full article
(This article belongs to the Special Issue Preclinical and Clinical Advances in Ovarian Cancer)
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13 pages, 571 KiB  
Review
Antibody-Drug Conjugates: A Promising Novel Therapy for the Treatment of Ovarian Cancer
by Aranzazu Manzano and Alberto Ocaña
Cancers 2020, 12(8), 2223; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12082223 - 09 Aug 2020
Cited by 17 | Viewed by 5434
Abstract
Antibody-drug conjugates (ADCs) represent a novel and promising therapeutic strategy for the treatment of cancer patients. ADCs target antigens highly expressed on the membrane surface of tumor cells to selectively deliver a cytotoxic drug. Ovarian tumors differentially express tumor-specific antigens, which can be [...] Read more.
Antibody-drug conjugates (ADCs) represent a novel and promising therapeutic strategy for the treatment of cancer patients. ADCs target antigens highly expressed on the membrane surface of tumor cells to selectively deliver a cytotoxic drug. Ovarian tumors differentially express tumor-specific antigens, which can be used to guide ADCs. This strategy allows for optimizing tumor targeting while minimizing systemic toxicity compared to classical chemotherapeutic agents. ADCs can be improved by using a cleavable linker allowing the delivery of the toxic payload in surrounding cells not expressing the target protein, therefore acting on heterogeneous tumors with different cell populations. Currently, more than 15 ADCs are under preclinical investigation in ovarian cancer, and some of them have already been tested in early-phase clinical trials with promising results. In this review, we summarize the mechanism of action and the toxicity profile of ADCs and discuss the latest preclinical discoveries and forthcoming applications in ovarian cancer. Full article
(This article belongs to the Special Issue Preclinical and Clinical Advances in Ovarian Cancer)
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25 pages, 671 KiB  
Review
PARP Inhibitor Resistance Mechanisms and Implications for Post-Progression Combination Therapies
by Elizabeth K. Lee and Ursula A. Matulonis
Cancers 2020, 12(8), 2054; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12082054 - 25 Jul 2020
Cited by 44 | Viewed by 5628
Abstract
The use of PARP inhibitors (PARPi) is growing widely as FDA approvals have shifted its use from the recurrence setting to the frontline setting. In parallel, the population developing PARPi resistance is increasing. Here we review the role of PARP, DNA damage repair, [...] Read more.
The use of PARP inhibitors (PARPi) is growing widely as FDA approvals have shifted its use from the recurrence setting to the frontline setting. In parallel, the population developing PARPi resistance is increasing. Here we review the role of PARP, DNA damage repair, and synthetic lethality. We discuss mechanisms of resistance to PARP inhibition and how this informs on novel combinations to re-sensitize cancer cells to PARPi. Full article
(This article belongs to the Special Issue Preclinical and Clinical Advances in Ovarian Cancer)
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35 pages, 1440 KiB  
Review
Preclinical and Clinical Immunotherapeutic Strategies in Epithelial Ovarian Cancer
by Alejandra Martinez, Jean-Pierre Delord, Maha Ayyoub and Christel Devaud
Cancers 2020, 12(7), 1761; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12071761 - 02 Jul 2020
Cited by 7 | Viewed by 4197
Abstract
In the past 20 years, the immune system has increasingly been recognized as a major player in tumor cell control, leading to considerable advances in cancer treatment. While promising with regards to melanoma, renal cancer and non-small cell lung cancer, immunotherapy provides, for [...] Read more.
In the past 20 years, the immune system has increasingly been recognized as a major player in tumor cell control, leading to considerable advances in cancer treatment. While promising with regards to melanoma, renal cancer and non-small cell lung cancer, immunotherapy provides, for the time being, limited success in other cancers, including ovarian cancer, potentially due to insufficient immunogenicity or to a particularly immunosuppressive microenvironment. In this review, we provide a global description of the immune context of ovarian cancer, in particular epithelial ovarian cancer (EOC). We describe the adaptive and innate components involved in the EOC immune response, including infiltrating tumor-specific T lymphocytes, B lymphocytes, and natural killer and myeloid cells. In addition, we highlight the rationale behind the use of EOC preclinical mouse models to assess resistance to immunotherapy, and we summarize the main preclinical studies that yielded anti-EOC immunotherapeutic strategies. Finally, we focus on major published or ongoing immunotherapy clinical trials concerning EOC. Full article
(This article belongs to the Special Issue Preclinical and Clinical Advances in Ovarian Cancer)
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18 pages, 1011 KiB  
Review
Overcoming Platinum and PARP-Inhibitor Resistance in Ovarian Cancer
by Michelle McMullen, Katherine Karakasis, Ainhoa Madariaga and Amit M. Oza
Cancers 2020, 12(6), 1607; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12061607 - 17 Jun 2020
Cited by 99 | Viewed by 9005
Abstract
Platinum chemotherapy remains the cornerstone of treatment for epithelial ovarian cancer (OC) and Poly (ADP-ribose) polymerase inhibitors (PARPi) now have an established role as maintenance therapy. The mechanisms of action of these agents is, in many ways, complementary, and crucially reliant on the [...] Read more.
Platinum chemotherapy remains the cornerstone of treatment for epithelial ovarian cancer (OC) and Poly (ADP-ribose) polymerase inhibitors (PARPi) now have an established role as maintenance therapy. The mechanisms of action of these agents is, in many ways, complementary, and crucially reliant on the intracellular DNA Damage Repair (DDR) response. Here, we review mechanisms of primary and acquired resistance to treatment with platinum and PARPi, examining the interplay between both classes of agents. A key resistance mechanism appears to be the restoration of the Homologous Recombination (HR) repair pathway, through BRCA reversion mutations and epigenetic upregulation of BRCA1. Alterations in non-homologous end-joint (NHEJ) repair, replication fork protection, upregulation of cellular drug efflux pumps, reduction in PARP1 activity and alterations to the tumour microenvironment have also been described. These resistance mechanisms reveal molecular vulnerabilities, which may be targeted to re-sensitise OC to platinum or PARPi treatment. Promising therapeutic strategies include ATR inhibition, epigenetic re-sensitisation through DNMT inhibition, cell cycle checkpoint inhibition, combination with anti-angiogenic therapy, BET inhibition and G-quadruplex stabilisation. Translational studies to elucidate mechanisms of treatment resistance should be incorporated into future clinical trials, as understanding these biologic mechanisms is crucial to developing new and effective therapeutic approaches in advanced OC. Full article
(This article belongs to the Special Issue Preclinical and Clinical Advances in Ovarian Cancer)
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29 pages, 1535 KiB  
Review
Galectins and Ovarian Cancer
by Chisa Shimada, Rui Xu, Linah Al-Alem, Marina Stasenko, David R. Spriggs and Bo R. Rueda
Cancers 2020, 12(6), 1421; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12061421 - 31 May 2020
Cited by 17 | Viewed by 5207
Abstract
Ovarian cancer is known for its aggressive pathological features, including the capacity to undergo epithelial to mesenchymal transition, promoting angiogenesis, metastatic potential, chemoresistance, inhibiting apoptosis, immunosuppression and promoting stem-like features. Galectins, a family of glycan-binding proteins defined by a conserved carbohydrate recognition domain, [...] Read more.
Ovarian cancer is known for its aggressive pathological features, including the capacity to undergo epithelial to mesenchymal transition, promoting angiogenesis, metastatic potential, chemoresistance, inhibiting apoptosis, immunosuppression and promoting stem-like features. Galectins, a family of glycan-binding proteins defined by a conserved carbohydrate recognition domain, can modulate many of these processes, enabling them to contribute to the pathology of ovarian cancer. Our goal herein was to review specific galectin members identified in the context of ovarian cancer, with emphasis on their association with clinical and pathological features, implied functions, diagnostic or prognostic potential and strategies being developed to disrupt their negative actions. Full article
(This article belongs to the Special Issue Preclinical and Clinical Advances in Ovarian Cancer)
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13 pages, 244 KiB  
Review
Therapeutic Approach to Low-Grade Serous Ovarian Carcinoma: State of Art and Perspectives of Clinical Research
by Angiolo Gadducci and Stefania Cosio
Cancers 2020, 12(5), 1336; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12051336 - 23 May 2020
Cited by 23 | Viewed by 5147
Abstract
Low-grade serous ovarian carcinoma (LGSOC) is a distinct pathologic and clinical entity, characterized by less aggressive biological behavior, lower sensitivity to chemotherapy and longer survival compared with high-grade serous ovarian carcinoma. LGSOC often harbors activating mutations of genes involved in mitogen activated protein [...] Read more.
Low-grade serous ovarian carcinoma (LGSOC) is a distinct pathologic and clinical entity, characterized by less aggressive biological behavior, lower sensitivity to chemotherapy and longer survival compared with high-grade serous ovarian carcinoma. LGSOC often harbors activating mutations of genes involved in mitogen activated protein kinase (MAPK) pathway. Patients with disease confined to the gonad(s) should undergo bilateral salpingo-oophorectomy, total hysterectomy and comprehensive surgical staging, although fertility-sparing surgery can be considered in selected cases. Women with stage IA-IB disease should undergo observation alone after surgery, whereas observation, chemotherapy or endocrine therapy are all possible options for those with stage IC-IIA disease. Patients with advanced disease should undergo primary debulking surgery with the aim of removing all macroscopically detectable disease, whereas neoadjuvant chemotherapy followed by interval debuking surgery. After surgery, the patients can receive either carboplatin plus paclitaxel followed by endocrine therapy or endocrine therapy alone. Molecularly targeted agents, and especially MEK inhibitors and Cyclin-dependent kinase (CDK) inhibitors, are currently under evaluation. Additional research on the genomics of LGSOC and clinical trials on the combination of MEK inhibitors with hormonal agents, other molecularly targeted agents or metformin, are strongly warranted to improve the prognosis of patients with this malignancy. Full article
(This article belongs to the Special Issue Preclinical and Clinical Advances in Ovarian Cancer)
23 pages, 1237 KiB  
Review
Exploiting the Prevalence of Homologous Recombination Deficiencies in High-Grade Serous Ovarian Cancer
by Sara Bouberhan, Lauren Philp, Sarah Hill, Linah F. Al-Alem and Bo Rueda
Cancers 2020, 12(5), 1206; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12051206 - 11 May 2020
Cited by 6 | Viewed by 4894
Abstract
High-grade serous ovarian cancer (HGSOC) remains the most lethal gynecologic cancer in the United States. Genomic analysis revealed roughly half of HGSOC display homologous repair deficiencies. An improved understanding of the genomic and somatic mutations that influence DNA repair led to the development [...] Read more.
High-grade serous ovarian cancer (HGSOC) remains the most lethal gynecologic cancer in the United States. Genomic analysis revealed roughly half of HGSOC display homologous repair deficiencies. An improved understanding of the genomic and somatic mutations that influence DNA repair led to the development of poly(ADP-ribose) polymerase inhibitors for the treatment of ovarian cancer. In this review, we explore the preclinical and clinical studies that led to the development of FDA approved drugs that take advantage of the synthetic lethality concept, the implementation of the early phase trials, the development of companion diagnostics and proposed mechanisms of resistance. Full article
(This article belongs to the Special Issue Preclinical and Clinical Advances in Ovarian Cancer)
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