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      Epigenetic Modifications as Therapeutic Targets

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      Author(s): 1 , 1 , 1
      Publication date (Electronic):
      Journal: Nature biotechnology

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          Abstract

          Epigenetic modifications work with genetic mechanisms to determine transcriptional activity and, while somatically heritable they are also reversible, making them good therapeutic candidates. Epigenetic changes can precede disease pathology and thus are diagnostic indicators for risk, and can act as prognostic indicators for disease progression. Histone deacetylase inhibitors and DNA methylation inhibitors have been FDA approved for several years and are clinically successful. More recently, histone methylation and microRNAs have also gained attention as potential therapeutic targets. The presence of multiple epigenetic aberrations within a diseased tissue and the abilities of cells to develop resistance suggest that combination therapies may be most beneficial. This review will focus on recent examples of using epigenetic modifications to evaluate disease risk, progression and clinical response and will describe the latest clinical advances in epigenetic therapies concentrating on treatments which combine epigenetic therapeutics with each other and with cytotoxic agents to increase clinical response.

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          Most cited references72

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          Epigenetics in cancer.

          S. Sharma, T. Kelly, P. Jones (2010)
          Epigenetic mechanisms are essential for normal development and maintenance of tissue-specific gene expression patterns in mammals. Disruption of epigenetic processes can lead to altered gene function and malignant cellular transformation. Global changes in the epigenetic landscape are a hallmark of cancer. The initiation and progression of cancer, traditionally seen as a genetic disease, is now realized to involve epigenetic abnormalities along with genetic alterations. Recent advancements in the rapidly evolving field of cancer epigenetics have shown extensive reprogramming of every component of the epigenetic machinery in cancer including DNA methylation, histone modifications, nucleosome positioning and non-coding RNAs, specifically microRNA expression. The reversible nature of epigenetic aberrations has led to the emergence of the promising field of epigenetic therapy, which is already making progress with the recent FDA approval of three epigenetic drugs for cancer treatment. In this review, we discuss the current understanding of alterations in the epigenetic landscape that occur in cancer compared with normal cells, the roles of these changes in cancer initiation and progression, including the cancer stem cell model, and the potential use of this knowledge in designing more effective treatment strategies.
          Article 0 comments Cited 805 times – based on 0 reviews     Review now
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            Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study.

            Pierre Fenaux, Ghulam J Mufti, Eva Hellstrom-Lindberg … (2009)
            Drug treatments for patients with high-risk myelodysplastic syndromes provide no survival advantage. In this trial, we aimed to assess the effect of azacitidine on overall survival compared with the three commonest conventional care regimens. In a phase III, international, multicentre, controlled, parallel-group, open-label trial, patients with higher-risk myelodysplastic syndromes were randomly assigned one-to-one to receive azacitidine (75 mg/m(2) per day for 7 days every 28 days) or conventional care (best supportive care, low-dose cytarabine, or intensive chemotherapy as selected by investigators before randomisation). Patients were stratified by French-American-British and international prognostic scoring system classifications; randomisation was done with a block size of four. The primary endpoint was overall survival. Efficacy analyses were by intention to treat for all patients assigned to receive treatment. This study is registered with ClinicalTrials.gov, number NCT00071799. Between Feb 13, 2004, and Aug 7, 2006, 358 patients were randomly assigned to receive azacitidine (n=179) or conventional care regimens (n=179). Four patients in the azacitidine and 14 in the conventional care groups received no study drugs but were included in the intention-to-treat efficacy analysis. After a median follow-up of 21.1 months (IQR 15.1-26.9), median overall survival was 24.5 months (9.9-not reached) for the azacitidine group versus 15.0 months (5.6-24.1) for the conventional care group (hazard ratio 0.58; 95% CI 0.43-0.77; stratified log-rank p=0.0001). At last follow-up, 82 patients in the azacitidine group had died compared with 113 in the conventional care group. At 2 years, on the basis of Kaplan-Meier estimates, 50.8% (95% CI 42.1-58.8) of patients in the azacitidine group were alive compared with 26.2% (18.7-34.3) in the conventional care group (p<0.0001). Peripheral cytopenias were the most common grade 3-4 adverse events for all treatments. Treatment with azacitidine increases overall survival in patients with higher-risk myelodysplastic syndromes relative to conventional care.
            Article 0 comments Cited 642 times – based on 0 reviews     Review now
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              Specific activation of microRNA-127 with downregulation of the proto-oncogene BCL6 by chromatin-modifying drugs in human cancer cells.

              Yoshimasa Saito, Gangning Liang, Gerda Egger … (2006)
              Expression profiling of T24 cells revealed that 17 out of 313 human miRNAs were upregulated more than 3-fold by simultaneous treatment with the chromatin-modifying drugs 5-aza-2'-deoxycytidine and 4-phenylbutyric acid. One of these, miR-127, is embedded in a CpG island and is highly induced from its own promoter after treatment. miR-127 is usually expressed as part of a miRNA cluster in normal cells but not in cancer cells, suggesting that it is subject to epigenetic silencing. In addition, the proto-oncogene BCL6, a potential target of miR-127, was translationally downregulated after treatment. These results suggest that DNA demethylation and histone deacetylase inhibition can activate expression of miRNAs that may act as tumor suppressors.
              Article 0 comments Cited 338 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 9604648
                Journal ID (pubmed-jr-id): 20305
                Journal ID (nlm-ta): Nat Biotechnol
                Title: Nature biotechnology
                ISSN (Print): 1087-0156
                ISSN (Electronic): 1546-1696
                Publication date Nihms-submitted: 7 September 2010
                Publication date (Electronic): 13 October 2010
                Publication date PMC-release: 1 April 2012
                Volume: 28
                Issue: 10
                Pages: 1069-1078
                Affiliations
                [1 ]Departments of Urology and Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA USA
                Author notes
                [2 ]To whom correspondence should be addressed. Tel: +1 323 865 0816; Fax +1 323 865 0102; pjones@ 123456med.usc.edu
                [*]

                These authors contributed equally to this work

                Article
                Manuscript ID: nihpa228695
                DOI: 10.1038/nbt.1678
                PMC ID: 3022972
                PubMed ID: 20944599
                SO-VID: 6150a262-d3c8-4dd3-a488-4f3e4e8f9bae
                License:

                Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

                History
                Funding
                Funded by: National Cancer Institute : NCI
                Award ID: R35 CA049758-12 ||CA
                Categories
                Subject: Article

                ScienceOpen disciplines: Biotechnology
                Data availability:
                ScienceOpen disciplines: Biotechnology

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