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      Wise Management of Ovarian Cancer: On the Cutting Edge

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          Abstract

          Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer mortality among women. Two-thirds of patients present at advanced stage at diagnosis, and the estimated 5 year survival rate is 20–40%. This heterogeneous group of malignancies has distinguishable etiology and molecular biology. Initially, single-gene sequencing was performed to identify germline DNA variations associated with EOC. However, hereditary EOC syndrome can be explained by germline pathogenic variants (gPVs) in several genes. In this regard, next-generation sequencing (NGS) changed clinical diagnostic testing, allowing assessment of multiple genes simultaneously in a faster and cheaper manner than sequential single gene analysis. As we move into the era of personalized medicine, there is evidence that poly (ADP-ribose) polymerase (PARP) inhibitors exploit homologous recombination (HR) deficiency, especially in breast cancer gene 1 and 2 ( BRCA1/2) mutation carriers. Furthermore, extensive preclinical data supported the development of aurora kinase (AURK) inhibitors in specific tumor types, including EOC. Their efficacy may be optimized in combination with chemotherapeutic or other molecular agents. The efficacy of metformin in ovarian cancer prevention is under investigation. Certain mutations, such as ARID1A mutations, and alterations in the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway, which are specific in ovarian clear cell carcinoma (OCCC) and endometrioid ovarian carcinoma (EnOC), may offer additional therapeutic targets in these clinical entities. Malignant ovarian germ cell tumors (MOGCTs) are rare and randomized trials are extremely challenging for the improvement of the existing management and development of novel strategies. This review attempts to offer an overview of the main aspects of ovarian cancer, catapulted from the molecular mechanisms to therapeutic considerations.

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          Most cited references91

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          Targeting EZH2 in cancer.

          Recent genomic studies have resulted in an emerging understanding of the role of chromatin regulators in the development of cancer. EZH2, a histone methyl transferase subunit of a Polycomb repressor complex, is recurrently mutated in several forms of cancer and is highly expressed in numerous others. Notably, both gain-of-function and loss-of-function mutations occur in cancers but are associated with distinct cancer types. Here we review the spectrum of EZH2-associated mutations, discuss the mechanisms underlying EZH2 function, and synthesize a unifying perspective that the promotion of cancer arises from disruption of the role of EZH2 as a master regulator of transcription. We further discuss EZH2 inhibitors that are now showing early signs of promise in clinical trials and also additional strategies to combat roles of EZH2 in cancer.
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            Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells.

            Metformin is used for the treatment of type 2 diabetes because of its ability to lower blood glucose. The effects of metformin are explained by the activation of AMP-activated protein kinase (AMPK), which regulates cellular energy metabolism. Recently, we showed that metformin inhibits the growth of breast cancer cells through the activation of AMPK. Here, we show that metformin inhibits translation initiation. In MCF-7 breast cancer cells, metformin treatment led to a 30% decrease in global protein synthesis. Metformin caused a dose-dependent specific decrease in cap-dependent translation, with a maximal inhibition of 40%. Polysome profile analysis showed an inhibition of translation initiation as metformin treatment of MCF-7 cells led to a shift of mRNAs from heavy to light polysomes and a concomitant increase in the amount of 80S ribosomes. The decrease in translation caused by metformin was associated with mammalian target of rapamycin (mTOR) inhibition, and a decrease in the phosphorylation of S6 kinase, ribosomal protein S6, and eIF4E-binding protein 1. The effects of metformin on translation were mediated by AMPK, as treatment of cells with the AMPK inhibitor compound C prevented the inhibition of translation. Furthermore, translation in MDA-MB-231 cells, which lack the AMPK kinase LKB1, and in tuberous sclerosis complex 2 null (TSC2(-/-)) mouse embryonic fibroblasts was unaffected by metformin, indicating that LKB1 and TSC2 are involved in the mechanism of action of metformin. These results show that metformin-mediated AMPK activation leads to inhibition of mTOR and a reduction in translation initiation, thus providing a possible mechanism of action of metformin in the inhibition of cancer cell growth.
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              Chromatin remodeling at DNA double-strand breaks.

              DNA double-strand breaks (DSBs) can arise from multiple sources, including exposure to ionizing radiation. The repair of DSBs involves both posttranslational modification of nucleosomes and concentration of DNA-repair proteins at the site of damage. Consequently, nucleosome packing and chromatin architecture surrounding the DSB may limit the ability of the DNA-damage response to access and repair the break. Here, we review early chromatin-based events that promote the formation of open, relaxed chromatin structures at DSBs and that allow the DNA-repair machinery to access the spatially confined region surrounding the DSB, thereby facilitating mammalian DSB repair. Copyright © 2013 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                J Pers Med
                J Pers Med
                jpm
                Journal of Personalized Medicine
                MDPI
                2075-4426
                21 May 2020
                June 2020
                : 10
                : 2
                : 41
                Affiliations
                [1 ]Medway NHS Foundation Trust, Windmill Road, Gillingham, Kent ME7 5NY, UK; matin.sheriff@ 123456nhs.net (M.S.); a.karathanasi@ 123456nhs.net (A.K.); agne.sadauskaite@ 123456nhs.net (A.S.)
                [2 ]AELIA Organization, 9th Km Thessaloniki—Thermi, 57001 Thessaloniki, Greece
                [3 ]St Luke’s Cancer Center, Royal Surrey County Hospital, Egerton Rd, Guildford GU2 7XX, UK; christos.mikropoulos@ 123456nhs.net
                [4 ]Division of Gynecology, University Hospital Zurich, Frauenklinikstrasse 10, CH-8091 Zürich, Switzerland; Eleftherios.Samartzis@ 123456usz.ch
                [5 ]Department of Oncology, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, P.O. Box 100, FI-00029 Helsinki, Finland; Peeter.Karihtala@ 123456oulu.fi
                [6 ]Cambridge University Hospitals NHS Foundation Trust, Hills Rd, Cambridge CB2 0QQ, UK; michelemoschetta1@ 123456gmail.com
                [7 ]Department of Cancer Medicine, Gustave Roussy Institut, 94805 Villejuif, France; elie.rassy@ 123456hotmail.com
                [8 ]Department of Hematology-Oncology, Hotel Dieu de France University Hospital, Faculty of Medicine, Saint Joseph University, Beirut 166830, Lebanon
                [9 ]Medical School, University of Ioannina, Stavros Niarchou Avenue, 45110 Ioannina, Greece; npavlid@ 123456uoi.gr
                Author notes
                [* ]Correspondence: stergiosboussios@ 123456gmail.com or stergios.boussios@ 123456nhs.net ; Tel.: +30-69-3862-5210 or +44-79-6038-2149
                Author information
                https://orcid.org/0000-0002-2512-6131
                Article
                jpm-10-00041
                10.3390/jpm10020041
                7354604
                32455595
                f3a74195-b960-4240-8ac4-17bd90fb4c05
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 29 April 2020
                : 19 May 2020
                Categories
                Review

                ovarian cancer,next-generation sequencing,homologous recombination repair,parp inhibitors,aurk inhibitors,metformin,personalized treatment

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