Topic Editors

National Cancer Institute, Bethesda, MD, USA
Eppley Institute and Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA

Advances in Ovarian Cancer Research: From Biology to Therapeutics

Abstract submission deadline
closed (28 February 2022)
Manuscript submission deadline
closed (31 May 2022)
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Topic Information

Dear Colleagues,

Recently, substantial progress has been made in treating ovarian cancer, predominantly based on the identification of new molecular targets. For example, PARP inhibitors have been successful largely due to their efficacy in cancers that harbor BRCA mutations or evidence of deficiency in the homologous recombination DNA repair pathway. This collection of articles will address the biological discoveries leading to the next breakthroughs in ovarian cancer research and treatment. Authors are encouraged to submit research studies with translational potential, especially those that include novel biomarkers for treatment effects. This topic thus provides a framework for integrating discoveries at the bench and the bedside.

Dr. Christina M. Annunziata
Prof. Dr. Adam R. Karpf
Topic Editors

Keywords

  • ovarian cancer
  • translational research
  • biomarkers
  • genetics
  • epigenetics
  • clinical trials
  • tumor biology
  • drug discovery

Participating Journals

Journal Name Impact Factor CiteScore Launched Year First Decision (median) APC
Biomolecules
biomolecules
5.5 8.3 2011 16.9 Days CHF 2700
Cancers
cancers
5.2 7.4 2009 17.9 Days CHF 2900
Cells
cells
6.0 9.0 2012 16.6 Days CHF 2700
Current Oncology
curroncol
2.6 2.6 1994 18 Days CHF 2200

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Published Papers (22 papers)

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11 pages, 3001 KiB  
Article
Genome-Wide Identification and Validation of Gene Expression Biomarkers in the Diagnosis of Ovarian Serous Cystadenocarcinoma
by Francesca Zalfa, Maria Grazia Perrone, Savina Ferorelli, Luna Laera, Ciro Leonardo Pierri, Anna Tolomeo, Vincenzo Dimiccoli, Giuseppe Perrone, Anna De Grassi and Antonio Scilimati
Cancers 2022, 14(15), 3764; https://doi.org/10.3390/cancers14153764 - 02 Aug 2022
Cited by 3 | Viewed by 1950
Abstract
Ovarian cancer is the second most prevalent gynecologic malignancy, and ovarian serous cystadenocarcinoma (OSCA) is the most common and lethal subtype of ovarian cancer. Current screening methods have strong limits on early detection, and the majority of OSCA patients relapse. In this work, [...] Read more.
Ovarian cancer is the second most prevalent gynecologic malignancy, and ovarian serous cystadenocarcinoma (OSCA) is the most common and lethal subtype of ovarian cancer. Current screening methods have strong limits on early detection, and the majority of OSCA patients relapse. In this work, we developed and cross-validated a method for detecting gene expression biomarkers able to discriminate OSCA tissues from healthy ovarian tissues and other cancer types with high accuracy. A preliminary ranking-based approach was applied, resulting in a panel of 41 over-expressed genes in OSCA. The RNA quantity gene expression of the 41 selected genes was then cross-validated by using NanoString nCounter technology. Moreover, we showed that the RNA quantity of eight genes (ADGRG1, EPCAM, ESRP1, MAL2, MYH14, PRSS8, ST14 and WFDC2) discriminates each OSCA sample from each healthy sample in our data set with sensitivity of 100% and specificity of 100%. For the other three genes (MUC16, PAX8 and SOX17) in combination, their RNA quantity may distinguish OSCA from other 29 tumor types. Full article
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17 pages, 2511 KiB  
Article
High-Volume Hospitals’ Ovarian Cancer Care—Less Individual Approach or Better Treatment Results?
by Sonja Millert-Kalińska, Dominik Pruski, Marcin Przybylski, Małgorzata Stawicka-Niełacna, Edyta Mądry and Radosław Mądry
Curr. Oncol. 2022, 29(8), 5278-5294; https://doi.org/10.3390/curroncol29080419 - 26 Jul 2022
Cited by 1 | Viewed by 1631
Abstract
Ovarian cancer (OC) is the eighth most common cancer worldwide and is usually diagnosed in advanced stages. The relationship between treatment in high-volume hospitals (HVHs) and survival in OC has been documented by multiple studies, which showed that superior treatment and survival outcomes [...] Read more.
Ovarian cancer (OC) is the eighth most common cancer worldwide and is usually diagnosed in advanced stages. The relationship between treatment in high-volume hospitals (HVHs) and survival in OC has been documented by multiple studies, which showed that superior treatment and survival outcomes are associated with surgical expertise and multidisciplinary resources. To our study, 135 first-time patients treated in the years 2019–2020 in the Department of Oncology of Poznań University of Medical Sciences were enrolled. Th analysis showed a significant dependency between being treated in a HVH from the beginning of one’s diagnosis and the scope of the first intervention. Additionally, among patients treated in our centre, a significant portion of patients underwent laparoscopy, and from one year to another the number of laparoscopies performed increased. This may indicate that more patients began to qualify for neoadjuvant treatment. Patients benefit the most from surgery in a centre with more experience in treating ovarian cancer. In the future, we will be able to expand this study by using data from patients treated before 2019 and analysing larger cohorts of patients. This might enable us to update the rates of overall survival (OS), objective response rate (ORR) and progression-free survival (PFS). Full article
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9 pages, 567 KiB  
Article
Does MIS Play a Role in the Treatment of Advanced Ovarian Cancer?
by Augusto Pereira, Javier F. Magrina, Paul M. Magtibay, Joao Siufi Neto, Daniela F. S. Siufi, Yu-Hui H. Chang and Tirso Perez-Medina
Cancers 2022, 14(15), 3579; https://doi.org/10.3390/cancers14153579 - 22 Jul 2022
Cited by 3 | Viewed by 1203
Abstract
Neoadjuvant chemotherapy allows a minimally invasive approach for interval debulking in patients with ovarian cancer considered unresectable to no residual disease by laparotomy at diagnosis. The aim of the study was to evaluate the type of surgical approach at interval debulking (ID) after [...] Read more.
Neoadjuvant chemotherapy allows a minimally invasive approach for interval debulking in patients with ovarian cancer considered unresectable to no residual disease by laparotomy at diagnosis. The aim of the study was to evaluate the type of surgical approach at interval debulking (ID) after three courses of carboplatin and taxol in patients with unresectable ovarian cancer at diagnosis compared with the type of surgical approach at primary debulking (PD). A secondary objective was to compare the perioperative outcomes of MIS vs. laparotomy at ID. A retrospective review of the type of surgical approach at ID following three courses of carboplatin and taxol was compared with the surgical approach at PD, and a review of the perioperative outcomes of MIS vs. open at ID was performed during the period from 21 January 2012, through 21 February 2013, for stage IIIC > 2 cm or IV epithelial ovarian cancer (EOC) unresectable at diagnosis and the surgical approach at PD. During the study period, 127 patients with stage IIIC or IV EOC met the inclusion criteria. Minimally invasive surgery (MIS), laparoscopic or robotic, was used in 21.6% of patients at ID and in 23.3% of patients at PD. At ID, MIS patients had a shorter hospital stay as compared to laparotomy (2 vs. 8 days; p < 0.001). At 5 year follow-up, 31.5% of EOC patients were alive (ID MIS: 47.5% vs. ID open: 30%; PD MIS: 41% vs. PD open: 28%), while 24.4% had no evidence of disease (ID MIS: 39% vs. ID open: 19.5%; PD MIS: 32% vs. PD open: 22%). Among living patients, 22% had evidence of disease. Neoadjuvant chemotherapy is a form of chemo-debulking and allows a minimally invasive approach at interval debulking in about one-fifth of the patients, with initial disease deemed unresectable to no residual tumor at initial diagnosis. Full article
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18 pages, 3236 KiB  
Article
A Novel ALDH1A1 Inhibitor Blocks Platinum-Induced Senescence and Stemness in Ovarian Cancer
by Vaishnavi Muralikrishnan, Fang Fang, Tyler C. Given, Ram Podicheti, Mikhail Chtcherbinine, Tara X. Metcalfe, Shruthi Sriramkumar, Heather M. O’Hagan, Thomas D. Hurley and Kenneth P. Nephew
Cancers 2022, 14(14), 3437; https://doi.org/10.3390/cancers14143437 - 15 Jul 2022
Cited by 11 | Viewed by 3139
Abstract
Ovarian cancer is a deadly disease attributed to late-stage detection as well as recurrence and the development of chemoresistance. Ovarian cancer stem cells (OCSCs) are hypothesized to be largely responsible for the emergence of chemoresistant tumors. Although chemotherapy may initially succeed at decreasing [...] Read more.
Ovarian cancer is a deadly disease attributed to late-stage detection as well as recurrence and the development of chemoresistance. Ovarian cancer stem cells (OCSCs) are hypothesized to be largely responsible for the emergence of chemoresistant tumors. Although chemotherapy may initially succeed at decreasing the size and number of tumors, it leaves behind residual malignant OCSCs. In this study, we demonstrate that aldehyde dehydrogenase 1A1 (ALDH1A1) is essential for the survival of OCSCs. We identified a first-in-class ALDH1A1 inhibitor, compound 974, and used 974 as a tool to decipher the mechanism of stemness regulation by ALDH1A1. The treatment of OCSCs with 974 significantly inhibited ALDH activity, the expression of stemness genes, and spheroid and colony formation. An in vivo limiting dilution assay demonstrated that 974 significantly inhibited CSC frequency. A transcriptomic sequencing of cells treated with 974 revealed a significant downregulation of genes related to stemness and chemoresistance as well as senescence and the senescence-associated secretory phenotype (SASP). We confirmed that 974 inhibited the senescence and stemness induced by platinum-based chemotherapy in functional assays. Overall, these data establish that ALDH1A1 is essential for OCSC survival and that ALDH1A1 inhibition suppresses chemotherapy-induced senescence and stemness. Targeting ALDH1A1 using small-molecule inhibitors in combination with chemotherapy therefore presents a promising strategy to prevent ovarian cancer recurrence and has the potential for clinical translation. Full article
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20 pages, 4351 KiB  
Article
Multiple Components of Protein Homeostasis Pathway Can Be Targeted to Produce Drug Synergies with VCP Inhibitors in Ovarian Cancer
by Prabhakar Bastola, Gary S. Leiserowitz and Jeremy Chien
Cancers 2022, 14(12), 2949; https://doi.org/10.3390/cancers14122949 - 15 Jun 2022
Cited by 3 | Viewed by 1974
Abstract
Protein quality control mechanisms play an important role in cancer progression by providing adaptive responses and morphologic stability against genome-wide copy number alterations, aneuploidy, and conformation-altering somatic mutations. This dependency on protein quality control mechanisms creates a vulnerability that may be exploited for [...] Read more.
Protein quality control mechanisms play an important role in cancer progression by providing adaptive responses and morphologic stability against genome-wide copy number alterations, aneuploidy, and conformation-altering somatic mutations. This dependency on protein quality control mechanisms creates a vulnerability that may be exploited for therapeutic benefits by targeting components of the protein quality control mechanism. Recently, valosin-containing protein (VCP), also known at p97 AAA-ATPase, has emerged as a druggable target in cancer cells to affect their dependency on protein quality control. Here, we show that VCP inhibitors induce cytotoxicity in several ovarian cancer cell lines and these compounds act synergistically with mifepristone, a drug previously shown to induce an atypical unfolded protein response. Although mifepristone at a clinically achievable dose induces a weak unfolded protein response, it enhances the cytotoxic effects of VCP inhibitor CB-5083. Mechanistically, mifepristone blocks the cytoprotective effect of ATF6 in response to endoplasmic reticulum (ER) stress while activating the cytotoxic effects of ATF4 and CHOP through the HRI (EIF2AK1)-mediated signal transduction pathway. In contrast, CB-5083 activates ATF4 and CHOP through the PERK (EIF2AK3)-mediated signaling pathway. This combination activates ATF4 and CHOP while blocking the adaptive response provided by ATF6, resulting in increased cytotoxic effects and synergistic drug interaction. Full article
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23 pages, 2447 KiB  
Review
Clinical Landscape of PARP Inhibitors in Ovarian Cancer: Molecular Mechanisms and Clues to Overcome Resistance
by Satoru Kyo, Kosuke Kanno, Masahiro Takakura, Hitomi Yamashita, Masako Ishikawa, Tomoka Ishibashi, Seiya Sato and Kentaro Nakayama
Cancers 2022, 14(10), 2504; https://doi.org/10.3390/cancers14102504 - 19 May 2022
Cited by 10 | Viewed by 3419
Abstract
The survival of patients with advanced or recurrent ovarian cancer has improved tremendously in the past decade, mainly due to the establishment of maintenance therapy with poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) after conservative chemotherapies. Despite their superior efficacy, resistance to PARPis has [...] Read more.
The survival of patients with advanced or recurrent ovarian cancer has improved tremendously in the past decade, mainly due to the establishment of maintenance therapy with poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) after conservative chemotherapies. Despite their superior efficacy, resistance to PARPis has been reported, and patients with resistance have a much worse prognosis. Therefore, the development of novel treatment strategies to overcome PARPi resistance is urgently needed. The present review article focuses on the molecular mechanisms of how PARPis exert cytotoxic effects on cancer cells through DNA repair processes, especially the genetic background and tumor microenvironment favored by PARPis. Furthermore, currently available information on PARPi resistance mechanisms is introduced and discussed to develop a novel therapeutic approach against them. Full article
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1 pages, 167 KiB  
Correction
Correction: Parashar et al. Patient-Derived Ovarian Cancer Spheroids Rely on PI3K-AKT Signaling Addiction for Cancer Stemness and Chemoresistance. Cancers 2022, 14, 958
by Deepak Parashar, Anjali Geethadevi, Sonam Mittal, Lindsey A. McAlarnen, Jasmine George, Ishaque P. Kadamberi, Prachi Gupta, Denise S. Uyar, Elizabeth E. Hopp, Holli Drendel, Erin A. Bishop, William H. Bradley, Kathleen M. Bone, Janet S. Rader, Sunila Pradeep and Pradeep Chaluvally-Raghavan
Cancers 2022, 14(10), 2443; https://doi.org/10.3390/cancers14102443 - 16 May 2022
Cited by 4 | Viewed by 1209
Abstract
The authors would like to correct the author byline to include Dr [...] Full article
23 pages, 1296 KiB  
Article
Understanding the Experience of Canadian Women Living with Ovarian Cancer through the Every Woman StudyTM
by Alicia Tone, Talin Boghosian, Alison Ross, Elisabeth Baugh, Alon D. Altman, Lesa Dawson, Frances Reid and Cailey Crawford
Curr. Oncol. 2022, 29(5), 3318-3340; https://doi.org/10.3390/curroncol29050271 - 05 May 2022
Viewed by 3462
Abstract
The Every Woman StudyTM: Canadian Edition is the most comprehensive study to date exploring patient-reported experiences of ovarian cancer (OC) on a national scale. An online survey conducted in Fall 2020 included individuals diagnosed with OC in Canada, reporting responses from [...] Read more.
The Every Woman StudyTM: Canadian Edition is the most comprehensive study to date exploring patient-reported experiences of ovarian cancer (OC) on a national scale. An online survey conducted in Fall 2020 included individuals diagnosed with OC in Canada, reporting responses from 557 women from 11 Canadian provinces/territories. Median age at diagnosis was 54 (11–80), 61% were diagnosed between 2016–2020, 59% were stage III/IV and all subtypes of OC were represented. Overall, 23% had a family history of OC, 75% had genetic testing and 19% reported having a BRCA1/2 mutation. Most (87%) had symptoms prior to diagnosis. A timely diagnosis of OC (≤3 months from first presentation with symptoms) was predicted by age (>50) or abdominal pain/persistent bloating as the primary symptom. Predictors of an acute diagnosis (<1 month) included region, ER/urgent care doctor as first healthcare provider or stage III/IV disease. Regional differences in genetic testing, treatments and clinical trial participation were also noted. Respondents cited substantial physical, emotional, practical and financial impacts of an OC diagnosis. Our national survey has revealed differences in the pathway to diagnosis and post-diagnostic care among Canadian women with OC, with region, initial healthcare provider, specific symptoms and age playing key roles. We have identified many opportunities to improve both clinical and supportive care of OC patients across the country. Full article
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18 pages, 1303 KiB  
Review
Tumor-Associated Macrophages and Ovarian Cancer: Implications for Therapy
by David Schweer, Annabel McAtee, Khaga Neupane, Christopher Richards, Frederick Ueland and Jill Kolesar
Cancers 2022, 14(9), 2220; https://doi.org/10.3390/cancers14092220 - 29 Apr 2022
Cited by 28 | Viewed by 5644
Abstract
The tumor microenvironment (TME) has been implicated to play an important role in the progression of ovarian cancer. One of the most important components of the TME is tumor associated macrophages (TAMs). Phenotypically, macrophages are broadly categorized as M1 pro-inflammatory or M2 anti-inflammatory, [...] Read more.
The tumor microenvironment (TME) has been implicated to play an important role in the progression of ovarian cancer. One of the most important components of the TME is tumor associated macrophages (TAMs). Phenotypically, macrophages are broadly categorized as M1 pro-inflammatory or M2 anti-inflammatory, based on the cytokines and chemokines that they secrete. The tumor microenvironment is associated with macrophages of an M2 phenotype which suppress the surrounding immune environment, assist tumor cells in evading immune targeting, and support tumor growth and metastasis. Contrarily, M1 macrophages help mount an immune response against tumors, and are associated with a more favorable prognosis in solid tumors. One of the characteristic indicators of a poor prognosis in ovarian cancer is the overrepresentation of M2-type TAMs. As such, therapeutic modalities targeting TME and TAMs are of increasing interest. Pharmacological approaches to eliminate TAMs, include decreasing macrophage survival and recruitment and increasing phagocytosis, have been underwhelming. Clinical strategies targeting these macrophage subtypes via repolarization to an M1 antitumoral state deserve increasing attention, and may serve as a new modality for immunotherapy. Full article
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12 pages, 1968 KiB  
Article
Biological Role of Tumor/Stromal CXCR4-CXCL12-CXCR7 in MITO16A/MaNGO-OV2 Advanced Ovarian Cancer Patients
by Crescenzo D’Alterio, Anna Spina, Laura Arenare, Paolo Chiodini, Maria Napolitano, Francesca Galdiero, Luigi Portella, Vittorio Simeon, Simona Signoriello, Francesco Raspagliesi, Domenica Lorusso, Carmela Pisano, Nicoletta Colombo, Gian Franco Zannoni, Nunzia Simona Losito, Rossella De Cecio, Giosuè Scognamiglio, Daniela Califano, Daniela Russo, Valentina Tuninetti, Maria Carmela Piccirillo, Piera Gargiulo, Francesco Perrone, Sandro Pignata and Stefania Scalaadd Show full author list remove Hide full author list
Cancers 2022, 14(7), 1849; https://doi.org/10.3390/cancers14071849 - 06 Apr 2022
Cited by 3 | Viewed by 2075
Abstract
This study investigated the prognostic role of the CXCR4-CXCL12-CXCR7 axis in advanced epithelial ovarian cancer (EOC) patients receiving first-line treatment within the MITO16A/MaNGO-OV2 phase-IV trial. CXCR4-CXCL12-CXCR7 expression was evaluated in the epithelial and stromal component of 308 EOC IHC-stained tumor samples. The statistical [...] Read more.
This study investigated the prognostic role of the CXCR4-CXCL12-CXCR7 axis in advanced epithelial ovarian cancer (EOC) patients receiving first-line treatment within the MITO16A/MaNGO-OV2 phase-IV trial. CXCR4-CXCL12-CXCR7 expression was evaluated in the epithelial and stromal component of 308 EOC IHC-stained tumor samples. The statistical analysis focused on biomarkers’ expression, their association with other variables and prognostic value. Zero-inflated tests, shrinkage, bootstrap procedures, and multivariable models were applied. The majority of EOC (75.0%) expressed CXCR4 and CXCR7, 56.5% expressed the entire CXCR4-CXCL12-CXCR7 axis, while only 4.6% were negative for CXCL12 and its cognate receptors, in regard to the epithelial component. Stromal CXCL12 and CXCR7, expressed in 11.2% and 65.5%, respectively, were associated with the FIGO stage. High CXCL12 in epithelial cancer cells was associated with shorter progression-free and overall survival. However, after adjusting for overfitting due to best cut-off multiplicity testing, the significance was lost. This is a wide-ranging, prospective study in which CXCR4-CXCL12-CXCR7 were systematically evaluated in epithelial and stromal components, in selected stage III-IV EOC. Although CXCL12 was not prognostic, epithelial expression identified high-risk FIGO stage III patients for PFS. These data suggest that it might be worth studying the CXCL12 axis as a therapeutic target to improve treatment efficacy in EOC patients. Full article
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12 pages, 2083 KiB  
Article
Feasibility of a Multimodal Prehabilitation Programme in Patients Undergoing Cytoreductive Surgery for Advanced Ovarian Cancer: A Pilot Study
by Berta Diaz-Feijoo, Nuria Agusti-Garcia, Raquel Sebio, Antonio López-Hernández, Marina Sisó, Ariel Glickman, Nuria Carreras-Dieguez, Pere Fuste, Tiermes Marina, Judit Martínez-Egea, Laura Aguilera, Juan Perdomo, Amaia Pelaez, Manuel López-Baamonde, Ricard Navarro-Ripoll, Elena Gimeno, Betina Campero, Aureli Torné, Graciela Martinez-Palli and María J. Arguis
Cancers 2022, 14(7), 1635; https://doi.org/10.3390/cancers14071635 - 23 Mar 2022
Cited by 13 | Viewed by 3267
Abstract
Introduction: Treatment for advanced ovarian cancer (AOC) comprises cytoreductive surgery combined with chemotherapy. Multimodal prehabilitation programmes before surgery have demonstrated efficacy in postoperative outcomes in non-gynaecological surgeries. However, the viability and effects of these programmes on patients with AOC are unknown. We aimed [...] Read more.
Introduction: Treatment for advanced ovarian cancer (AOC) comprises cytoreductive surgery combined with chemotherapy. Multimodal prehabilitation programmes before surgery have demonstrated efficacy in postoperative outcomes in non-gynaecological surgeries. However, the viability and effects of these programmes on patients with AOC are unknown. We aimed to evaluate the feasibility and postoperative impact of a multimodal prehabilitation programme in AOC patients undergoing surgery. Methods: This single-centre, before-and-after intervention pilot study included 34 patients in two cohorts: the prehabilitation cohort prospectively included 15 patients receiving supervised exercise, nutritional optimisation, and psychological preparation from December 2019 to January 2021; the control cohort included 19 consecutive patients between January 2018 and November 2019. Enhanced Recovery After Surgery guidelines were followed. Results: The overall adherence to the multimodal prehabilitation programme was 80%, with 86.7% adherence to exercise training, 100% adherence to nutritional optimisation, and 80% adherence to psychological preparation. The median hospital stay was shorter in the prehabilitation cohort (5 (IQR, 4–6) vs. 7 days (IQR, 5–9) in the control cohort, p = 0.04). Differences in postoperative complications using the comprehensive complication index (CCI) were not significant (CCI score: 9.3 (SD 12.12) in the prehabilitation cohort vs. 16.61 (SD 16.89) in the control cohort, p = 0.08). The median time to starting chemotherapy was shorter in the prehabilitation cohort (25 (IQR, 23–25) vs. 35 days (IQR, 28–45) in the control cohort, p = 0.03). Conclusions: A multimodal prehabilitation programme before cytoreductive surgery is feasible in AOC patients with no major adverse effects, and results in significantly shorter hospital stays and time to starting chemotherapy. Full article
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14 pages, 22688 KiB  
Article
Long Non-Coding RNA-Based Functional Prediction Reveals Novel Targets in Notch-Upregulated Ovarian Cancer
by Seonhyang Jeong, Sunmi Park, Young Suk Jo, Moon Jung Choi, Gibbeum Lee, Seul Gi Lee, Min Chul Choi, Hyun Park, Won Duk Joo, Sang Geun Jung and Jandee Lee
Cancers 2022, 14(6), 1557; https://doi.org/10.3390/cancers14061557 - 18 Mar 2022
Cited by 3 | Viewed by 1770
Abstract
Notch signaling is a druggable target in high-grade serous ovarian cancers; however, its complexity is not clearly understood. Recent revelations of the biological roles of lncRNAs have led to an increased interest in the oncogenic action of lncRNAs in various cancers. In this [...] Read more.
Notch signaling is a druggable target in high-grade serous ovarian cancers; however, its complexity is not clearly understood. Recent revelations of the biological roles of lncRNAs have led to an increased interest in the oncogenic action of lncRNAs in various cancers. In this study, we performed in silico analyses using The Cancer Genome Atlas data to discover novel Notch-related lncRNAs and validated our transcriptome data via NOTCH1/3 silencing in serous ovarian cancer cells. The expression of novel Notch-related lncRNAs was down-regulated by a Notch inhibitor and was upregulated in high-grade serous ovarian cancers, compared to benign or borderline ovarian tumors. Functionally, Notch-related lncRNAs were tightly linked to Notch-related changes in diverse gene expressions. Notably, genes related to DNA repair and spermatogenesis showed specific correlations with Notch-related lncRNAs. Master transcription factors, including EGR1, CTCF, GABPα, and E2F4 might orchestrate the upregulation of Notch-related lncRNAs, along with the associated genes. The discovery of Notch-related lncRNAs significantly contributes to our understanding of the complex crosstalk of Notch signaling with other oncogenic pathways at the transcriptional level. Full article
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18 pages, 23832 KiB  
Article
Distinct Genomic Profiles Are Associated with Treatment Response and Survival in Ovarian Cancer
by Chris J. de Witte, Joachim Kutzera, Arne van Hoeck, Luan Nguyen, Ingrid A. Boere, Mathilde Jalving, Petronella B. Ottevanger, Christa van Schaik-van de Mheen, Marion Stevense, Wigard P. Kloosterman, Ronald P. Zweemer, Edwin Cuppen and Petronella O. Witteveen
Cancers 2022, 14(6), 1511; https://doi.org/10.3390/cancers14061511 - 15 Mar 2022
Cited by 4 | Viewed by 2609
Abstract
The majority of patients with ovarian cancer ultimately develop recurrent chemotherapy-resistant disease. Treatment stratification is mainly based on histological subtype and stage, prior response to platinum-based chemotherapy, and time to recurrent disease. Here, we integrated clinical treatment, treatment response, and survival data with [...] Read more.
The majority of patients with ovarian cancer ultimately develop recurrent chemotherapy-resistant disease. Treatment stratification is mainly based on histological subtype and stage, prior response to platinum-based chemotherapy, and time to recurrent disease. Here, we integrated clinical treatment, treatment response, and survival data with whole-genome sequencing profiles of 132 solid tumor biopsies of metastatic epithelial ovarian cancer to explore genome-informed stratification opportunities. Samples from primary and recurrent disease harbored comparable numbers of single nucleotide variants and structural variants. Mutational signatures represented platinum exposure, homologous recombination deficiency, and aging. Unsupervised hierarchical clustering based on genomic input data identified specific ovarian cancer subgroups, characterized by homologous recombination deficiency, genome stability, and duplications. The clusters exhibited distinct response rates and survival probabilities which could thus potentially be used for genome-informed therapy stratification for more personalized ovarian cancer treatment. Full article
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20 pages, 8036 KiB  
Article
Patient-Derived Ovarian Cancer Spheroids Rely on PI3K-AKT Signaling Addiction for Cancer Stemness and Chemoresistance
by Deepak Parashar, Anjali Geethadevi, Sonam Mittal, Lindsey A. McAlarnen, Jasmine George, Ishaque P. Kadamberi, Prachi Gupta, Denise S. Uyar, Elizabeth E. Hopp, Holli Drendel, Erin A. Bishop, William H. Bradley, Kathleen M. Bone, Janet S. Rader, Sunila Pradeep and Pradeep Chaluvally-Raghavan
Cancers 2022, 14(4), 958; https://doi.org/10.3390/cancers14040958 - 15 Feb 2022
Cited by 13 | Viewed by 2914 | Correction
Abstract
Ovarian cancer is the most lethal gynecological malignancy among women worldwide and is characterized by aggressiveness, cancer stemness, and frequent relapse due to resistance to platinum-based therapy. Ovarian cancer cells metastasize through ascites fluid as 3D spheroids which are more resistant to apoptosis [...] Read more.
Ovarian cancer is the most lethal gynecological malignancy among women worldwide and is characterized by aggressiveness, cancer stemness, and frequent relapse due to resistance to platinum-based therapy. Ovarian cancer cells metastasize through ascites fluid as 3D spheroids which are more resistant to apoptosis and chemotherapeutic agents. However, the precise mechanism as an oncogenic addiction that makes 3D spheroids resistant to apoptosis and chemotherapeutic agents is not understood. To study the signaling addiction mechanism that occurs during cancer progression in patients, we developed an endometrioid subtype ovarian cancer cell line named ‘MCW-OV-SL-3’ from the ovary of a 70-year-old patient with stage 1A endometrioid adenocarcinoma of the ovary. We found that the cell line MCW-OV-SL-3 exhibits interstitial duplication of 1q (q21–q42), where this duplication resulted in high expression of the PIK3C2B gene and aberrant activation of PI3K-AKT-ERK signaling. Using short tandem repeat (STR) analysis, we demonstrated that the cell line exhibits a unique genetic identity compared to existing ovarian cancer cell lines. Notably, the MCW-OV-SL-3 cell line was able to form 3D spheroids spontaneously, which is an inherent property of tumor cells when plated on cell culture dishes. Importantly, the tumor spheroids derived from the MCW-OV-SL-3 cell line expressed high levels of c-Kit, PROM1, ZEB1, SNAI, VIM, and Twist1 compared to 2D monolayer cells. We also observed that the hyperactivation of ERK and PI3K/AKT signaling in these cancer cells resulted in resistance to cisplatin. In summary, the MCW-OV-SL3 endometrioid cell line is an excellent model to study the mechanism of cancer stemness and chemoresistance in endometrioid ovarian cancer. Full article
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16 pages, 1646 KiB  
Article
Phase 2 Trial (POLA Study) of Lurbinectedin plus Olaparib in Patients with Advanced Solid Tumors: Results of Efficacy, Tolerability, and the Translational Study
by Andres Poveda, Raquel Lopez-Reig, Ana Oaknin, Andres Redondo, Maria Jesus Rubio, Eva Guerra, Lorena Fariñas-Madrid, Alejandro Gallego, Victor Rodriguez-Freixinos, Antonio Fernandez-Serra, Oscar Juan, Ignacio Romero and Jose A. Lopez-Guerrero
Cancers 2022, 14(4), 915; https://doi.org/10.3390/cancers14040915 - 12 Feb 2022
Cited by 4 | Viewed by 3291
Abstract
We hypothesized that the combination of olaparib and lurbinectedin maximizes DNA damage, thus increasing its efficacy. The POLA phase 1 trial established the recommended phase 2 dose of lurbinectedin as being 1.5 mg (day 1) and that of olaparib as being 250 mg/12 [...] Read more.
We hypothesized that the combination of olaparib and lurbinectedin maximizes DNA damage, thus increasing its efficacy. The POLA phase 1 trial established the recommended phase 2 dose of lurbinectedin as being 1.5 mg (day 1) and that of olaparib as being 250 mg/12 h (days 1–5) for a 21-day cycle. In phase 2, we explore the efficacy of the combination in terms of clinical response and its correlation with mutations in the HRR genes and the genomic instability (GI) parameters. Results: A total of 73 patients with high-grade ovarian (n = 46), endometrial (n = 26), and triple-negative breast cancer (n = 1) were treated with lurbinectedin and olaparib. Most patients (62%) received ≥3 lines of prior therapy. The overall response rate (ORR) and disease control rate (DCR) were 9.6% and 72.6%, respectively. The median progression-free survival (PFS) was 4.54 months (95% CI 3.0–5.2). Twelve (16.4%) patients were considered long-term responders (LTR), with a median PFS of 13.3 months. No clinical benefit was observed for cases with HRR gene mutation. In ovarian LTRs, although a direct association with GI and a total loss of heterozygosity (LOH) events was observed, the association did not reach statistical significance (p = 0.055). Globally, the total number of LOHs might be associated with the ORR (p =0.074). The most common grade 3–4 toxicities were anemia and thrombocytopenia, in 6 (8.2%) and 3 (4.1%) patients, respectively. Conclusion: The POLA study provides evidence that the administration of lurbinectedin and olaparib is feasible and tolerable, with a DCR of 72.6%. Different GI parameters showed associations with better responses. Full article
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16 pages, 1638 KiB  
Review
Hereditary Ovarian Carcinoma: Cancer Pathogenesis Looking beyond BRCA1 and BRCA2
by David Samuel, Alexandra Diaz-Barbe, Andre Pinto, Matthew Schlumbrecht and Sophia George
Cells 2022, 11(3), 539; https://doi.org/10.3390/cells11030539 - 04 Feb 2022
Cited by 17 | Viewed by 5879
Abstract
Besides BRCA1 and BRCA2, several other inheritable mutations have been identified that increase ovarian cancer risk. Surgical excision of the fallopian tubes and ovaries reduces ovarian cancer risk, but for some non-BRCA hereditary ovarian cancer mutations the benefit of this intervention [...] Read more.
Besides BRCA1 and BRCA2, several other inheritable mutations have been identified that increase ovarian cancer risk. Surgical excision of the fallopian tubes and ovaries reduces ovarian cancer risk, but for some non-BRCA hereditary ovarian cancer mutations the benefit of this intervention is unclear. The fallopian tubes of women with hereditary ovarian cancer mutations provide many insights into the early events of carcinogenesis and process of malignant transformation. Here we review cancer pathogenesis in hereditary cases of ovarian cancer, the occurrence of pre-invasive lesions and occult carcinoma in mutation carriers and their clinical management. Full article
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14 pages, 3030 KiB  
Article
Beyond BRCA1/2: Homologous Recombination Repair Genetic Profile in a Large Cohort of Apulian Ovarian Cancers
by Antonella Turchiano, Daria Carmela Loconte, Rosalba De Nola, Francesca Arezzo, Giulia Chiarello, Antonino Pantaleo, Matteo Iacoviello, Rosanna Bagnulo, Annunziata De Luisi, Sonia Perrelli, Stefania Martino, Carlotta Ranieri, Antonella Garganese, Alessandro Stella, Cinzia Forleo, Vera Loizzi, Marco Marinaccio, Ettore Cicinelli, Gennaro Cormio and Nicoletta Resta
Cancers 2022, 14(2), 365; https://doi.org/10.3390/cancers14020365 - 12 Jan 2022
Cited by 6 | Viewed by 2368
Abstract
Background: Pathogenic variants in homologous recombination repair (HRR) genes other than BRCA1/2 have been associated with a high risk of ovarian cancer (OC). In current clinical practice, genetic testing is generally limited to BRCA1/2. Herein, we investigated the mutational status of both [...] Read more.
Background: Pathogenic variants in homologous recombination repair (HRR) genes other than BRCA1/2 have been associated with a high risk of ovarian cancer (OC). In current clinical practice, genetic testing is generally limited to BRCA1/2. Herein, we investigated the mutational status of both BRCA1/2 and 5 HRR genes in 69 unselected OC, evaluating the advantage of multigene panel testing in everyday clinical practice. Methods: We analyzed 69 epithelial OC samples using an NGS custom multigene panel of the 5 HRR pathways genes, beyond the genetic screening routine of BRCA1/2 testing. Results: Overall, 19 pathogenic variants (27.5%) were detected. The majority (21.7%) of patients displayed a deleterious mutation in BRCA1/2, whereas 5.8% harbored a pathogenic variant in one of the HRR genes. Additionally, there were 14 (20.3%) uncertain significant variants (VUS). The assessment of germline mutational status showed that a small number of variants (five) were not detected in the corresponding blood sample. Notably, we detected one BRIP1 and four BRCA1/2 deleterious variants in the low-grade serous and endometrioid histology OC, respectively. Conclusion: We demonstrate that using a multigene panel beyond BRCA1/2 improves the diagnostic yield in OC testing, and it could produce clinically relevant results. Full article
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17 pages, 3877 KiB  
Article
Multi-Marker Immunofluorescent Staining and PD-L1 Detection on Circulating Tumour Cells from Ovarian Cancer Patients
by Du-Bois Asante, Michael Morici, Ganendra R. K. A. Mohan, Emmanuel Acheampong, Isaac Spencer, Weitao Lin, Paula van Miert, Samantha Gibson, Aaron B. Beasley, Melanie Ziman, Leslie Calapre, Tarek M. Meniawy and Elin S. Gray
Cancers 2021, 13(24), 6225; https://doi.org/10.3390/cancers13246225 - 10 Dec 2021
Cited by 6 | Viewed by 3493
Abstract
Detection of ovarian cancer (OC) circulating tumour cells (CTCs) is primarily based on targeting epithelial markers, thus failing to detect mesenchymal tumour cells. More importantly, the immune checkpoint inhibitor marker PD-L1 has not been demonstrated on CTCs from OC patients. An antibody staining [...] Read more.
Detection of ovarian cancer (OC) circulating tumour cells (CTCs) is primarily based on targeting epithelial markers, thus failing to detect mesenchymal tumour cells. More importantly, the immune checkpoint inhibitor marker PD-L1 has not been demonstrated on CTCs from OC patients. An antibody staining protocol was developed and tested using SKOV-3 and OVCA432 OC cell lines. We targeted epithelial (cytokeratin (CK) and EpCAM), mesenchymal (vimentin), and OC-specific (PAX8) markers for detection of CTCs, and CD45/16 and CD31 were used for the exclusion of white blood and vascular endothelial cells, respectively. PD-L1 was used for CTC characterisation. CTCs were enriched using the Parsortix™ system from 16 OC patients. Results revealed the presence of CTCs in 10 (63%) cases. CTCs were heterogeneous, with 113/157 (72%) cells positive for CK/EpCAM (epithelial marker), 58/157 (37%) positive for vimentin (mesenchymal marker), and 17/157 (11%) for both (hybrid). PAX8 was only found in 11/157 (7%) CTCs. In addition, 62/157 (39%) CTCs were positive for PD-L1. Positivity for PD-L1 was significantly associated with the hybrid phenotype when compared with the epithelial (p = 0.007) and mesenchymal (p = 0.0009) expressing CTCs. Characterisation of CTC phenotypes in relation to clinical outcomes is needed to provide insight into the role that epithelial to mesenchymal plasticity plays in OC and its relationship with PD-L1. Full article
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24 pages, 4509 KiB  
Article
Epigenetic Therapy Augments Classic Chemotherapy in Suppressing the Growth of 3D High-Grade Serous Ovarian Cancer Spheroids over an Extended Period of Time
by Michelle Bilbao, Chelsea Katz, Stephanie L. Kass, Devon Smith, Krystal Hunter, David Warshal, James K. Aikins and Olga Ostrovsky
Biomolecules 2021, 11(11), 1711; https://doi.org/10.3390/biom11111711 - 17 Nov 2021
Cited by 4 | Viewed by 2110
Abstract
Recurrent high-grade serous ovarian cancer (HGSC) is clinically very challenging and prematurely shortens patients’ lives. Recurrent ovarian cancer is characterized by high tumor heterogeneity; therefore, it is susceptible to epigenetic therapy in classic 2D tissue culture and rodent models. Unfortunately, this success has [...] Read more.
Recurrent high-grade serous ovarian cancer (HGSC) is clinically very challenging and prematurely shortens patients’ lives. Recurrent ovarian cancer is characterized by high tumor heterogeneity; therefore, it is susceptible to epigenetic therapy in classic 2D tissue culture and rodent models. Unfortunately, this success has not translated well into clinical trials. Utilizing a 3D spheroid model over a period of weeks, we were able to compare the efficacy of classic chemotherapy and epigenetic therapy on recurrent ovarian cancer cells. Unexpectedly, in our model, a single dose of paclitaxel alone caused the exponential growth of recurrent high-grade serous epithelial ovarian cancer over a period of weeks. In contrast, this effect is not only opposite under treatment with panobinostat, but panobinostat reverses the repopulation of cancer cells following paclitaxel treatment. In our model, we also demonstrate differences in the drug-treatment sensitivity of classic chemotherapy and epigenetic therapy. Moreover, 3D-derived ovarian cancer cells demonstrate induced proliferation, migration, invasion, cancer colony formation and chemoresistance properties after just a single exposure to classic chemotherapy. To the best of our knowledge, this is the first evidence demonstrating a critical contrast between short and prolonged post-treatment outcomes following classic chemotherapy and epigenetic therapy in recurrent high-grade serous ovarian cancer in 3D culture. Full article
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15 pages, 2367 KiB  
Article
Highly Expressed Progesterone Receptor B Isoform Increases Platinum Sensitivity and Survival of Ovarian High-Grade Serous Carcinoma
by Hao Lin, Kuo-Chung Lan, Yu-Che Ou, Chen-Hsuan Wu, Hong-Yo Kang, I-Chieh Chuang and Hung-Chun Fu
Cancers 2021, 13(21), 5578; https://doi.org/10.3390/cancers13215578 - 08 Nov 2021
Cited by 3 | Viewed by 2137
Abstract
Background: Expression of the progesterone receptor (PR) has been reported to influence survival outcomes in patients with ovarian high-grade serous carcinoma (HGSC). In the present study, we attempted to investigate the association among PR and its isoforms’ expression, platinum sensitivity, and survival in [...] Read more.
Background: Expression of the progesterone receptor (PR) has been reported to influence survival outcomes in patients with ovarian high-grade serous carcinoma (HGSC). In the present study, we attempted to investigate the association among PR and its isoforms’ expression, platinum sensitivity, and survival in ovarian HGSC. Material and methods: This retrospective study reviewed ovarian HGSC patients who received surgery followed by adjuvant chemotherapy. We analyzed total PR and PR isoform-B (PR-B) expression by immunohistochemical staining and quantified using the H-score. Then, we compared platinum sensitivity and survival outcomes between those patients with weak and strong PR-B expression. Cisplatin viability assays were carried out in ovarian HGSC cell lines (OC-3-VGH and OVCAR-3) with different PR-B expression. Results: Among 90 patients, 49 and 41 patients were considered to have platinum-sensitive and platinum-resistant disease, respectively. Pearson’s correlation model showed that the H-score of total PR correlated positively with PR-B (r = 0.813). The PR-B H-score of tumors was significantly higher in the platinum-sensitive group (p = 0.004). Multivariate analysis revealed that the PR-B H-score and optimal debulking status were independent factors predicting platinum sensitivity. When compared with strong PR-B expression, patients with weak PR-B had significantly poorer progression-free (p = 0.021) and cancer-specific survival (p = 0.046). In a cell model, cisplatin-resistant OC-3-VGH cells expressed a lower level of PR-B than wild-type cells. Overexpression of PR-B or progesterone could increase cisplatin sensitivity in both OC-3-VGH and OVCAR-3 cells via the mechanism of promoting cisplatin-related apoptosis. Conclusions: When compared to weak PR-B, ovarian HGSC patients with a strong PR-B expression had a better chance of platinum sensitivity and survival, and this finding was compatible with our experimental results. Progesterone seemed to be a platinum sensitizer, but the value of adding progesterone in the treatment of ovarian HGSC should be further investigated. Full article
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13 pages, 16190 KiB  
Article
Voltage-Gated Sodium Channels as Potential Biomarkers and Therapeutic Targets for Epithelial Ovarian Cancer
by Iris S. Brummelhuis, Stephen J. Fiascone, Kathleen T. Hasselblatt, Gyorgy Frendl and Kevin M. Elias
Cancers 2021, 13(21), 5437; https://doi.org/10.3390/cancers13215437 - 29 Oct 2021
Cited by 11 | Viewed by 2325
Abstract
Abnormal ion channel expression distinguishes several types of carcinoma. Here, we explore the relationship between voltage-gated sodium channels (VGSC) and epithelial ovarian cancer (EOC). We find that EOC cell lines express most VGSC, but at lower levels than fallopian tube secretory epithelial cells [...] Read more.
Abnormal ion channel expression distinguishes several types of carcinoma. Here, we explore the relationship between voltage-gated sodium channels (VGSC) and epithelial ovarian cancer (EOC). We find that EOC cell lines express most VGSC, but at lower levels than fallopian tube secretory epithelial cells (the cells of origin for most EOC) or control fibroblasts. Among patient tumor samples, lower SCN8A expression was associated with improved overall survival (OS) (median 111 vs. 52 months; HR 2.04 95% CI: 1.21–3.44; p = 0.007), while lower SCN1B expression was associated with poorer OS (median 45 vs. 56 months; HR 0.69 95% CI 0.54–0.87; p = 0.002). VGSC blockade using either anti-epileptic drugs or local anesthetics (LA) decreased the proliferation of cancer cells. LA increased cell line sensitivity to platinum and taxane chemotherapies. While lidocaine had similar additive effects with chemotherapy among EOC cells and fibroblasts, bupivacaine showed a more pronounced impact on EOC than fibroblasts when combined with either carboplatin (ΔAUC −37% vs. −16%, p = 0.003) or paclitaxel (ΔAUC −37% vs. −22%, p = 0.02). Together, these data suggest VGSC are prognostic biomarkers in EOC and may inform new targets for therapy. Full article
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26 pages, 5024 KiB  
Article
Peanut-Shaped Gold Nanoparticles with Shells of Ceragenin CSA-131 Display the Ability to Inhibit Ovarian Cancer Growth In Vitro and in a Tumor Xenograft Model
by Ewelina Piktel, Ilona Oscilowska, Łukasz Suprewicz, Joanna Depciuch, Natalia Marcińczyk, Ewa Chabielska, Przemysław Wolak, Katarzyna Głuszek, Justyna Klimek, Piotr M. Zieliński, Michał T. Marzec, Paul B. Savage, Magdalena Parlińska-Wojtan and Robert Bucki
Cancers 2021, 13(21), 5424; https://doi.org/10.3390/cancers13215424 - 29 Oct 2021
Cited by 7 | Viewed by 2503
Abstract
Gold nanoparticles-assisted delivery of antineoplastics into cancerous cells is presented as an effective approach for overcoming the limitations of systemic chemotherapy. Although ceragenins show great potential as anti-cancer agents, in some tumors, effective inhibition of cancer cells proliferation requires application of ceragenins at [...] Read more.
Gold nanoparticles-assisted delivery of antineoplastics into cancerous cells is presented as an effective approach for overcoming the limitations of systemic chemotherapy. Although ceragenins show great potential as anti-cancer agents, in some tumors, effective inhibition of cancer cells proliferation requires application of ceragenins at doses within their hemolytic range. For the purpose of toxicity/efficiency ratio control, peanut-shaped gold nanoparticles (AuP NPs) were functionalized with a shell of ceragenin CSA-131 and the cytotoxicity of AuP@CSA-131 against ovarian cancer SKOV-3 cells and were then analyzed. In vivo efficiency of intravenously and intratumorally administered CSA-131 and AuP@CSA-131 was examined using a xenograft ovarian cancer model. Serum parameters were estimated using ELISA methods. Comparative analysis revealed that AuP@CSA-131 exerted stronger anti-cancer effects than free ceragenin, which was determined by enhanced ability to induce caspase-dependent apoptosis and autophagy processes via reactive oxygen species (ROS)-mediated pathways. In an animal study, AuP@CSA-131 was characterized by delayed clearance and prolonged blood circulation when compared with free ceragenin, as well as enhanced anti-tumor efficiency, particularly when applied intratumorally. Administration of CSA-131 and AuP@CSA-131 prevented the inflammatory response associated with cancer development. These results present the possibility of employing non-spherical gold nanoparticles as an effective nanoplatform for the delivery of antineoplastics for the treatment of ovarian malignancy. Full article
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