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Preclinical and Translational Research in Gynecological Cancers

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Pathophysiology".

Deadline for manuscript submissions: closed (5 August 2022) | Viewed by 18800

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Dr. Daniela Gallo

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Unit of Translational Medicine for Woman and Child Health, Department of Woman, Child and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; Department of Life Sciences and Public Health, Section of Gynaecology and Obstetrics, Università Cattolica del Sacro Cuore, Rome, Italy
Interests: ovarian cancer; gynecological malignancies; translational research; molecular biology; chemoresistance diagnostic; prognostic and predictive biomarker discovery; experimental therapeutics; toxicology

Dr. Claudia Marchetti

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Gynecologic Oncology Unit, Department of Woman, Child and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, 31-00168 Rome, Italy
Interests: ovarian cancer; target therapies; chemotherapy; homologous recombination; BRCA; platinum resistance; PARP inhibitors
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Special Issue Information

Dear Colleagues,

Uterine, ovarian, cervical, vulvar, and vaginal cancer represent the most common gynecologic malignancies affecting human female reproductive organs. These are different diseases, with different signs, symptoms, risk factors, etiology, treatment, and prognosis. During the last decade, high-throughput genomic analyses of single tumors have allowed the identification of important molecular targets or pathways driving gynecological cancers, thus enabling the development of personalized therapies. However, despite the great progress in the surgical and clinical management, gynecologic malignancies remain a major cause of morbidity and mortality worldwide. Therefore, there is an urgent need of further investigations that could effectively implement cancer diagnosis, prognosis, and treatment. Many conceptual and methodological biological questions remain to be answered by preclinical translational research, as prerequisite for the clinical development of new treatment strategies to overcome drug resistance and finally improve patient survival.

This Special Issue focuses on the current state of the art and future opportunities related to Preclinical and Translational Research in the field of Gynecological Cancers. The Issue will therefore include new original research articles and timely reviews from experts in the field of gynecologic cancer in basic/preclinical and translational research areas.

Dr. Daniela Gallo
Dr. Claudia Marchetti
Guest Editors

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Keywords

gynecological malignancies
translational research
molecular biology
carcinogenesis
chemoresistance
genomic instability
homologous recombination disease
biomarkers
target therapies
PARP inhibitors

Published Papers (8 papers)

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Research

18 pages, 2915 KiB

Open AccessArticle

What’s beyond BRCA Mutational Status in High Grade Serous Ovarian Cancer? The Impact of Hormone Receptor Expression in a Large BRCA-Profiled Ovarian Cancer Patient Series: A Retrospective Cohort Study

by Emanuele Perrone, Riccardo Tudisco, Pia Clara Pafundi, Davide Guido, Alessandra Ciucci, Enrica Martinelli, Gian Franco Zannoni, Alessia Piermattei, Saveria Spadola, Giulia Ferrante, Claudia Marchetti, Giovanni Scambia, Anna Fagotti and Daniela Gallo

Cancers 2022, 14(19), 4588; https://doi.org/10.3390/cancers14194588 - 22 Sep 2022

Viewed by 1444

Abstract

Several studies have explored the prognostic role of hormone receptor status in high-grade serous ovarian cancer (HGSOC) patients. However, few reports have investigated their expression according to BRCA mutational status. The aim of this single-center, observational, retrospective study was to explore the hormone receptor pattern and its potential prognostic role in a cohort of 207 HGSOC women stratified for BRCA mutational status. To this end, ERα, ERβ1, ERβ2, ERβ5, PR, and AR expression were assessed by immunohistochemistry in 135 BRCA-wild type (BRCA-wt) and 72 BRCA1/2 mutation carriers (BRCA-mut). No significant difference emerged in hormone receptor expression between the two sub-samples, except for a significantly lower ERα expression observed in pre-menopausal BRCA1/2-mut as compared to BRCA-wt patients (p = 0.02). None of the examined hormone receptors has revealed a significant prognostic role in the whole sample, apart from the ratio ERα/ERβ5 nuclear, for which higher values disclosed a positive role on the outcome in BRCA-wt subgroup (HR 0.77; CI 0.61–0.96; p = 0.019). Conversely, it negatively affected overall survival in the presence of BRCA1/2-mut (HR 1.41; CI 1.06–1.87; p = 0.020). Finally, higher PR levels were associated with platinum sensitivity in the whole sample (p = 0.019). Our data, though needing further validation, suggest a potential role of oestrogen-mediated pathways in BRCA1/2-associated HGSOC tumorigenesis, thus revealing a possible therapeutic potential for targeting this interaction. Full article

(This article belongs to the Special Issue Preclinical and Translational Research in Gynecological Cancers)

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19 pages, 6433 KiB

Open AccessArticle

The Peptide-Drug Conjugate TH1902: A New Sortilin Receptor-Mediated Cancer Therapeutic against Ovarian and Endometrial Cancers

by Jean-Christophe Currie, Michel Demeule, Cyndia Charfi, Alain Zgheib, Alain Larocque, Bogdan Alexandru Danalache, Amira Ouanouki, Richard Béliveau, Christian Marsolais and Borhane Annabi

Cancers 2022, 14(8), 1877; https://doi.org/10.3390/cancers14081877 - 08 Apr 2022

Cited by 10 | Viewed by 2882

Abstract

Sortilin (SORT1) receptor-mediated endocytosis functions were exploited for this new approach for effective and safe treatments of gynecological cancers. Here, high expression of SORT1 was found in >75% of the clinically annotated ovarian and endometrial tumors analyzed by immunohistochemistry. Therefore, the anticancer properties of the peptide-drug conjugate TH1902, a peptide that targets SORT1 and which is linked to docetaxel molecules, were investigated both in vitro using ovarian and endometrial cancer cell cultures and in vivo using xenograft models. In vitro, TH1902 inhibited cell proliferation and triggered higher SORT1-dependent cell apoptosis than unconjugated docetaxel did in ES-2 and SKOV3 ovarian cancer cell lines. The uptake of the Alexa⁴⁸⁸-TH19P01 peptide from TH1902 was reduced upon siRNA-mediated silencing of SORT1. In vivo, weekly administration of TH1902 showed better tolerability compared to equivalent docetaxel doses and inhibited tumor growth in ovarian and endometrial xenograft mice models. TH1902 as a single agent inhibited ovarian tumor growth more than either of the unconjugated taxanes or carboplatin. Furthermore, TH1902 combination with carboplatin also demonstrated better efficacy when compared to both taxanes-carboplatin combinations. Overall, TH1902 shows better in vivo efficacy, compared to that of docetaxel and even paclitaxel, against SORT1-positive ovarian and endometrial cancers and could be safely combined with carboplatin. Full article

(This article belongs to the Special Issue Preclinical and Translational Research in Gynecological Cancers)

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15 pages, 2749 KiB

Open AccessFeature PaperArticle

PD-L1 Expression on Circulating Tumour-Derived Microvesicles as a Complementary Tool for Stratification of High-Grade Serous Ovarian Cancer Patients

by Alessandra Battaglia, Alessia Piermattei, Alexia Buzzonetti, Tina Pasciuto, Nicole Zampetti, Marco Fossati, Giuseppe Angelico, Valentina Iacobelli, Camilla Nero, Veronica Iannucci, Giovanni Scambia, Anna Fagotti and Andrea Fattorossi

Cancers 2021, 13(20), 5200; https://doi.org/10.3390/cancers13205200 - 16 Oct 2021

Cited by 7 | Viewed by 1917

Abstract

Background: Ovarian cancer (OC) has recently attracted attention for the use of PD-1/PD-L1 axis blocking agents, with durable activity reported only in a subset of patients. The most used biomarker for sensitivity to the PD-1/PD-L1 axis blockade is tumour PD-L1 status by immunohistochemistry. However, patient stratification using this method suffers from intrinsic heterogeneity of OC, likely contributing to the unsatisfactory results obtained so far. Cells communicate with each other by releasing microvesicles (MVs) that carry parental cell surface features. Thus, we hypothesised that PD-L1⁺ tumour cells (TC) and infiltrating PD-L1⁺ leukocytes should shed MVs carrying surface PD-L1 that may serve as a proxy for the whole tumour PD-L1 status. Results: We showed for the first time the presence of measurable amounts of TC- and leukocyte-derived PD-L1⁺ MVs (range: 1.4–178.8 MVs/μL and 6.2–504.8 MVs/μL, respectively) in the plasma of high-grade serous OC (HGSOC) patients (n = 63), using a sensitive flow cytometry platform. The concentration of PD-L1⁺ MVs of either origin did not associate with the PD-L1 status of TCs and leukocytes in the tumour biopsies, suggesting that the circulating PD-L1⁺ MVs also included ones from locations not selected for immunohistochemistry analysis and represented the PD-L1 status of the whole tumour mass. In this study, we also describe the serendipitous discovery of circulating PD-L1⁺ MVs of platelet origin (10.3–2409.6 MVs/μL). Conclusions: The enumeration of circulating PD-L1⁺ MVs in HGSOC patients may provide a novel direction for assessing the tumour PD-L1 status and contribute to HGSOC patient stratification for immunotherapy interventions. The presence of circulating PD-L1⁺ MVs of platelet origin, a finding not yet reported in HGSOC patients, warrants further studies. Full article

(This article belongs to the Special Issue Preclinical and Translational Research in Gynecological Cancers)

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15 pages, 13174 KiB

Open AccessArticle

Evaluation of Angiogenesis-Related Genes as Prognostic Biomarkers of Bevacizumab Treated Ovarian Cancer Patients: Results from the Phase IV MITO16A/ManGO OV-2 Translational Study

by Daniela Califano, Daniela Gallo, Gian Luca Rampioni Vinciguerra, Rossella De Cecio, Laura Arenare, Simona Signoriello, Daniela Russo, Gabriella Ferrandina, Francesca Citron, Nunzia Simona Losito, Piera Gargiulo, Vittorio Simeon, Giovanni Scambia, Sabrina Chiara Cecere, Marco Montella, Nicoletta Colombo, Germana Tognon, Eliana Bignotti, Gian Franco Zannoni, Vincenzo Canzonieri, Alessandra Ciucci, Anna Spina, Giosuè Scognamiglio, Michele Del Sesto, Clorinda Schettino, Maria Carmela Piccirillo, Francesco Perrone, Paolo Chiodini, Sandro Pignata and Gustavo Baldassarre Show full author list Hide full author list

Cancers 2021, 13(20), 5152; https://doi.org/10.3390/cancers13205152 - 14 Oct 2021

Cited by 7 | Viewed by 2304

Abstract

Background. Epithelial ovarian cancer (EOC) is a rare, highly lethal disease. In a subset of high grade EOC patients, maintenance therapy with the antiangiogenic drug Bevacizumab (BEV) is a valuable option. To date, no validated predictive or prognostic biomarkers exist for selecting EOC patients that might benefit from BEV treatment. Methods. Immunohistochemistry and RT-qPCR evaluated the expression of seven angiogenesis-related proteins and of a twelve microRNAs angio-signature in EOC patients, treated in first line with chemotherapy plus BEV (MITO16A/ManGO OV-2 phase IV trial). Centralized statistical analyses assessed the associations between each biomarker, clinical prognostic factors and survival outcomes. Results. High miR-484 expression was associated with longer progression-free and overall survival. Notably, the combined expression of miR-484 and its target VEGFB identified a subset of patients that might mostly benefit from BEV treatment. No other significant correlations were found between the other analyzed biomarkers and patients’ survival. The application of a shrinkage procedure to adjust for over-fitting hazard ratio estimates reduced the association significance. Conclusions. The analysis of angiogenesis related biomarkers in EOC patients homogenously treated with BEV in first line provides novel insight in their prognostic value and suggests that some of them might merit to be tested as predictive markers of drug activity in dedicated randomized trials. Full article

(This article belongs to the Special Issue Preclinical and Translational Research in Gynecological Cancers)

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16 pages, 1499 KiB

Open AccessArticle

Comprehensive Profiling of Hypoxia-Related miRNAs Identifies miR-23a-3p Overexpression as a Marker of Platinum Resistance and Poor Prognosis in High-Grade Serous Ovarian Cancer

by Paola Todeschini, Elisa Salviato, Chiara Romani, Vittoria Raimondi, Francesco Ciccarese, Federico Ferrari, Germana Tognon, Sergio Marchini, Maurizio D’Incalci, Laura Zanotti, Antonella Ravaggi, Franco Odicino, Enrico Sartori, Donna M. D’Agostino, Michele Samaja, Chiara Romualdi and Eliana Bignotti

Cancers 2021, 13(13), 3358; https://doi.org/10.3390/cancers13133358 - 04 Jul 2021

Cited by 9 | Viewed by 2421

Abstract

The onset of chemo-resistant recurrence represents the principal cause of high-grade serous ovarian carcinoma (HGSOC) death. HGSOC masses are characterized by a hypoxic microenvironment, which contributes to the development of this chemo-resistant phenotype. Hypoxia regulated-miRNAs (HRMs) represent a molecular response of cancer cells to hypoxia and are involved in tumor progression. We investigated the expression of HRMs using miRNA expression data from a total of 273 advanced-stage HGSOC samples. The miRNAs associated with chemoresistance and survival were validated by RT-qPCR and target prediction, and comparative pathway analysis was conducted for target gene identification. Analysis of miRNA expression profiles indicated miR-23a-3p and miR-181c-5p over-expression as associated with chemoresistance and poor PFS. RT-qPCR data confirmed upregulation of miR-23a-3p in tumors from chemoresistant HGSOC patients and its significant association with shorter PFS. In silico miR-23a-3p target prediction and comparative pathway analysis identified platinum drug resistance as the pathway with the highest number of miR-23a-3p target genes. Among them, APAF-1 emerged as the most promising, being downregulated in platinum-resistant patients and in HGSOC chemo-resistant cells. These results highlight miR-23a-3p as a potential biomarker for HGSOC platinum response and prognosis and the miR23a-3p/APAF1 axis as a possible target to overcome platinum-resistance. Full article

(This article belongs to the Special Issue Preclinical and Translational Research in Gynecological Cancers)

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16 pages, 33220 KiB

Open AccessFeature PaperArticle

PARP1-Inhibition Sensitizes Cervical Cancer Cell Lines for Chemoradiation and Thermoradiation

by Marloes IJff, Gregor G. W. van Bochove, Denise Whitton, Roy Winiarczyk, Celina Honhoff, Hans Rodermond, Johannes Crezee, Lukas J. A. Stalpers, Nicolaas A. P. Franken and Arlene L. Oei

Cancers 2021, 13(9), 2092; https://doi.org/10.3390/cancers13092092 - 26 Apr 2021

Cited by 4 | Viewed by 2794

Abstract

Radiotherapy plus cisplatin (chemoradiation) is standard treatment for women with locoregionally advanced cervical cancer. Both radiotherapy and cisplatin induce DNA single and double-strand breaks (SSBs and DSBs). These double-strand breaks can be repaired via two major DNA repair pathways: Classical Non-Homologous End-Joining (cNHEJ) and Homologous Recombination. Besides inducing DNA breaks, cisplatin also disrupts the cNHEJ pathway. Patients contra-indicated for cisplatin are treated with radiotherapy plus hyperthermia (thermoradiation). Hyperthermia inhibits the HR pathway. The aim of our study is to enhance chemoradiation or thermoradiation by adding PARP1-inhibition, which disrupts both the SSB repair and the Alternative NHEJ DSB repair pathway. This was studied in cervical cancer cell lines (SiHa, HeLa, C33A and CaSki) treated with hyperthermia (42 °C) ± ionizing radiation (2–6 Gy) ± cisplatin (0.3–0.5 µM) ± PARP1-inhibitor (olaparib, 4.0–5.0 µM). Clonogenic assays were performed to measure cell reproductive death. DSBs were analyzed by γ-H2AX staining and cell death by live cell imaging. Both chemoradiation and thermoradiation resulted in lower survival fractions and increased unrepaired DSBs when combined with a PARP1-inhibitor. A quadruple modality, including ionizing radiation, hyperthermia, cisplatin and PARP1-i, was not more effective than either triple modality. However, both chemoradiation and thermoradiation benefit significantly from additional treatment with PARP1-i. Full article

(This article belongs to the Special Issue Preclinical and Translational Research in Gynecological Cancers)

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19 pages, 4373 KiB

Open AccessArticle

Structural Bases for the Synergistic Inhibition of Human Thymidylate Synthase and Ovarian Cancer Cell Growth by Drug Combinations

by Cecilia Pozzi, Matteo Santucci, Gaetano Marverti, Domenico D’Arca, Lorenzo Tagliazucchi, Stefania Ferrari, Gaia Gozzi, Lorena Losi, Giusy Tassone, Stefano Mangani, Glauco Ponterini and Maria Paola Costi

Cancers 2021, 13(9), 2061; https://doi.org/10.3390/cancers13092061 - 24 Apr 2021

Cited by 2 | Viewed by 1999

Abstract

Combining drugs represent an approach to efficiently prevent and overcome drug resistance and to reduce toxicity; yet it is a highly challenging task, particularly if combinations of inhibitors of the same enzyme target are considered. To show that crystallographic and inhibition kinetic information can provide indicators of cancer cell growth inhibition by combinations of two anti-human thymidylate synthase (hTS) drugs, we obtained the X-ray crystal structure of the hTS:raltitrexed:5-fluorodeoxyuridine monophosphate (FdUMP) complex. Its analysis showed a ternary complex with both molecules strongly bound inside the enzyme catalytic cavity. The synergistic inhibition of hTS and its mechanistic rationale were consistent with the structural analysis. When administered in combination to A2780 and A2780/CP ovarian cancer cells, the two drugs inhibited ovarian cancer cell growth additively/synergistically. Together, these results support the idea that X-ray crystallography can provide structural indicators for designing combinations of hTS (or any other target)-directed drugs to accelerate preclinical research for therapeutic application. Full article

(This article belongs to the Special Issue Preclinical and Translational Research in Gynecological Cancers)

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8 pages, 490 KiB

Open AccessCommunication

Prognostic Evidence of the miRNA-Based Ovarian Cancer Signature MiROvaR in Independent Datasets

by Loris De Cecco, Marina Bagnoli, Paolo Chiodini, Sandro Pignata and Delia Mezzanzanica

Cancers 2021, 13(7), 1544; https://doi.org/10.3390/cancers13071544 - 27 Mar 2021

Cited by 5 | Viewed by 1701

Abstract

Epithelial ovarian cancer (EOC) remains the second most common cause of gynecological cancer deaths. To improve patients’ outcomes, we still need reliable biomarkers of early relapse, of which external independent validation is a crucial process. Our previously established prognostic signature, MiROvaR, including 35 microRNAs (miRNA) able to stratify EOC patients for their risk of relapse, was challenged on a new independent cohort of 197 EOC patients included in the Pelvic Mass Study whose miRNA profile was made publically available, thus resulting in the only accessible database aside from the EOC TCGA collection. Following accurate data matrix adjustment to account for the use of different miRNA platforms, MiROvaR confirmed its ability to discriminate early relapsing patients. The model’s original cutoff separated 156 (79.2%) high- and 41 (20.8%) low-risk patients with median progression free survival (PFS) of 16.3 months and not yet reached (NYR), respectively (hazard ratio (HR): 2.42–95% Confidence Interval (CI) 1.49–3.93; Log-rank p = 0.00024). The MiROvaR predictive accuracy (area under the curve (AUC) = 0.68; 95% Cl 0.57–0.79) confirms its prognostic value. This external validation in a totally independently collected, handled and profiled EOC cohort suggests that MiROvaR is a strong and reliable biomarker of EOC early relapse, warranting prospective validation. Full article

(This article belongs to the Special Issue Preclinical and Translational Research in Gynecological Cancers)

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