Early epigenetic changes and DNA damage do not predict clinical response in an overlapping schedule of 5-azacytidine and entinostat in patients with myeloid malignancies
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- Tamer E. Fandy
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD;
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- James G. Herman
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD;
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- Patrick Kerns
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD;
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- Anchalee Jiemjit
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD;
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- Elizabeth A. Sugar
- Departments of Epidemiology and Biostatistics, The Bloomberg School of Public Health at Johns Hopkins University, Baltimore, MD;
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- Si-Ho Choi
- Division of Hematology, University of Southern California, Norris Cancer Center, Los Angeles;
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- Allen S. Yang
- Division of Hematology, University of Southern California, Norris Cancer Center, Los Angeles;
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- Timothy Aucott
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD;
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- Tianna Dauses
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD;
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- Rosalie Odchimar-Reissig
- Division of Medical Oncology, Mount Sinai Medical Center, New York, NY;
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- Jonathan Licht
- Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL;
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- Melanie J. McConnell
- Malaghan Institute of Medical Research, Wellington, New Zealand;
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- Chris Nasrallah
- Center for Theoretical Evolutionary Genetics, University of California, Berkeley;
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- Marianne K. H. Kim
- Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL;
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- Weijia Zhang
- Division of Hematology/Oncology, Mount Sinai School of Medicine, New York, NY;
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- Yezou Sun
- Personalized Medicine Research Program, Mount Sinai School of Medicine, New York, NY; and
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- Anthony Murgo
- Cancer Therapy Evaluation Program, National Cancer Institute, Rockville, MD
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- Igor Espinoza-Delgado
- Cancer Therapy Evaluation Program, National Cancer Institute, Rockville, MD
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- Katharine Oteiza
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD;
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- Ibitayo Owoeye
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD;
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- Lewis R. Silverman
- Division of Medical Oncology, Mount Sinai Medical Center, New York, NY;
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- Steven D. Gore
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD;
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- Hetty E. Carraway
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD;
書誌事項
- 公開日
- 2009-09-24
- DOI
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- 10.1182/blood-2009-02-203547
- 公開者
- American Society of Hematology
この論文をさがす
説明
<jats:title>Abstract</jats:title> <jats:p>Sequential administration of DNA methyltransferase (DNMT) inhibitors and histone deacetylase (HDAC) inhibitors has demonstrated clinical efficacy in patients with hematologic malignancies. However, the mechanism behind their clinical efficacy remains controversial. In this study, the methylation dynamics of 4 TSGs (p15INK4B, CDH-1, DAPK-1, and SOCS-1) were studied in sequential bone marrow samples from 30 patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) who completed a minimum of 4 cycles of therapy with 5-azacytidine and entinostat. Reversal of promoter methylation after therapy was observed in both clinical responders and nonresponders across all genes. There was no association between clinical response and either baseline methylation or methylation reversal in the bone marrow or purified CD34+ population, nor was there an association with change in gene expression. Transient global hypomethylation was observed in samples after treatment but was not associated with clinical response. Induction of histone H3/H4 acetylation and the DNA damage–associated variant histone γ-H2AX was observed in peripheral blood samples across all dose cohorts. In conclusion, methylation reversal of candidate TSGs during cycle 1 of therapy was not predictive of clinical response to combination “epigenetic” therapy. This trial is registered with http://www.clinicaltrials.gov under NCT00101179.</jats:p>
収録刊行物
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- Blood
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Blood 114 (13), 2764-2773, 2009-09-24
American Society of Hematology