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      DNMTi/HDACi combined epigenetic targeted treatment induces reprogramming of myeloma cells in the direction of normal plasma cells

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          Abstract

          Background

          Multiple myeloma (MM) is the second most common hematologic malignancy. Aberrant epigenetic modifications have been reported in MM and could be promising therapeutic targets. As response rates are overall limited but deep responses occur, it is important to identify those patients who could indeed benefit from epigenetic-targeted therapy.

          Methods

          Since HDACi and DNMTi combination have potential therapeutic value in MM, we aimed to build a GEP-based score that could be useful to design future epigenetic-targeted combination trials. In addition, we investigated the changes in GEP upon HDACi/DNMTi treatment.

          Results

          We report a new gene expression-based score to predict MM cell sensitivity to the combination of DNMTi/HDACi. A high Combo score in MM patients identified a group with a worse overall survival but a higher sensitivity of their MM cells to DNMTi/HDACi therapy compared to a low Combo score. In addition, treatment with DNMTi/HDACi downregulated IRF4 and MYC expression and appeared to induce a mature BMPC plasma cell gene expression profile in myeloma cell lines.

          Conclusion

          In conclusion, we developed a score for the prediction of primary MM cell sensitivity to DNMTi/HDACi and found that this combination could be beneficial in high-risk patients by targeting proliferation and inducing maturation.

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          Most cited references59

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          The molecular classification of multiple myeloma.

          To better define the molecular basis of multiple myeloma (MM), we performed unsupervised hierarchic clustering of mRNA expression profiles in CD138-enriched plasma cells from 414 newly diagnosed patients who went on to receive high-dose therapy and tandem stem cell transplants. Seven disease subtypes were validated that were strongly influenced by known genetic lesions, such as c-MAF- and MAFB-, CCND1- and CCND3-, and MMSET-activating translocations and hyperdiploidy. Indicative of the deregulation of common pathways by gene orthologs, common gene signatures were observed in cases with c-MAF and MAFB activation and CCND1 and CCND3 activation, the latter consisting of 2 subgroups, one characterized by expression of the early B-cell markers CD20 and PAX5. A low incidence of focal bone disease distinguished one and increased expression of proliferation-associated genes of another novel subgroup. Comprising varying fractions of each of the other 6 subgroups, the proliferation subgroup dominated at relapse, suggesting that this signature is linked to disease progression. Proliferation and MMSET-spike groups were characterized by significant overexpression of genes mapping to chromosome 1q, and both exhibited a poor prognosis relative to the other groups. A subset of cases with a predominating myeloid gene expression signature, excluded from the profiling analyses, had more favorable baseline characteristics and superior prognosis to those lacking this signature.
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            A validated gene expression model of high-risk multiple myeloma is defined by deregulated expression of genes mapping to chromosome 1.

            To molecularly define high-risk disease, we performed microarray analysis on tumor cells from 532 newly diagnosed patients with multiple myeloma (MM) treated on 2 separate protocols. Using log-rank tests of expression quartiles, 70 genes, 30% mapping to chromosome 1 (P < .001), were linked to early disease-related death. Importantly, most up-regulated genes mapped to chromosome 1q, and down-regulated genes mapped to chromosome 1p. The ratio of mean expression levels of up-regulated to down-regulated genes defined a high-risk score present in 13% of patients with shorter durations of complete remission, event-free survival, and overall survival (training set: hazard ratio [HR], 5.16; P < .001; test cohort: HR, 4.75; P < .001). The high-risk score also was an independent predictor of outcome endpoints in multivariate analysis (P < .001) that included the International Staging System and high-risk translocations. In a comparison of paired baseline and relapse samples, the high-risk score frequency rose to 76% at relapse and predicted short postrelapse survival (P < .05). Multivariate discriminant analysis revealed that a 17-gene subset could predict outcome as well as the 70-gene model. Our data suggest that altered transcriptional regulation of genes mapping to chromosome 1 may contribute to disease progression, and that expression profiling can be used to identify high-risk disease and guide therapeutic interventions.
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              Combination epigenetic therapy has efficacy in patients with refractory advanced non-small cell lung cancer.

              Epigenetic alterations are strongly associated with the development of cancer. We conducted a phase I/II trial of combined epigenetic therapy with azacitidine and entinostat, inhibitors of DNA methylation and histone deacetylation, respectively, in extensively pretreated patients with recurrent metastatic non-small cell lung cancer. This therapy is well tolerated, and objective responses were observed, including a complete response and a partial response in a patient who remains alive and without disease progression approximately 2 years after completing protocol therapy. Median survival in the entire cohort was 6.4 months (95% CI 3.8-9.2), comparing favorably with existing therapeutic options. Demethylation of a set of 4 epigenetically silenced genes known to be associated with lung cancer was detectable in serial blood samples in these patients and was associated with improved progression-free (P = 0.034) and overall survival (P = 0.035). Four of 19 patients had major objective responses to subsequent anticancer therapies given immediately after epigenetic therapy. This study demonstrates that combined epigenetic therapy with low-dose azacitidine and entinostat results in objective, durable responses in patients with solid tumors and defines a blood-based biomarker that correlates with clinical benefit.
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                Author and article information

                Contributors
                +33 04 67 33 79 03 , jerome.moreaux@igh.cnrs.fr
                Journal
                Br J Cancer
                Br. J. Cancer
                British Journal of Cancer
                Nature Publishing Group UK (London )
                0007-0920
                1532-1827
                2 March 2018
                2 March 2018
                April 2018
                : 118
                : 8
                : 1062-1073
                Affiliations
                [1 ]ISNI 0000 0000 9886 5504, GRID grid.462268.c, IGH, CNRS, Univ Montpellier, ; Montpellier, France
                [2 ]ISNI 0000 0001 2290 8069, GRID grid.8767.e, Laboratory of Hematology and Immunology, Myeloma Center Brussels, , Vrije Universiteit Brussel, ; Brussels, Belgium
                [3 ]ISNI 0000 0000 9961 060X, GRID grid.157868.5, Department of Biological Haematology, , CHU Montpellier, ; Montpellier, France
                [4 ]ISNI 0000 0001 2190 4373, GRID grid.7700.0, Dept. of Internal Medicine V, , University of Heidelberg, ; Heidelberg, Germany
                [5 ]ISNI 0000 0001 2097 0141, GRID grid.121334.6, UFR de Médecine, Univ Montpellier, ; Montpellier, France
                [6 ]ISNI 0000 0000 9961 060X, GRID grid.157868.5, Department of Clinical Hematology, , CHU Montpellier, ; Montpellier, France
                [7 ]ISNI 0000 0001 2097 0141, GRID grid.121334.6, Univ Montpellier, ; UMR CNRS 5235, Montpellier, France
                [8 ]ISNI 0000 0001 2190 4373, GRID grid.7700.0, National Center of Tumor Diseases, , University of Heidelberg, ; Heidelberg, Germany
                Article
                25
                10.1038/s41416-018-0025-x
                5931098
                29500406
                8f64a981-29e6-49a4-8868-3bf53990ad30
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. If you remix, transform, or build upon this article or a part thereof, you must distribute your contributions under the same license as the original. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/.

                History
                : 7 August 2017
                : 10 January 2018
                : 15 January 2018
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                © Cancer Research UK 2018

                Oncology & Radiotherapy
                Oncology & Radiotherapy

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