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

被引：232

作者：

Fandy, Tamer E. ^{[1
]}

Herman, James G. ^{[1
]}

Kerns, Patrick ^{[1
]}

Jiemjit, Anchalee ^{[1
]}

Sugar, Elizabeth A. ^{[2
,3
]}

Choi, Si-Ho ^{[4
]}

Yang, Allen S. ^{[4
]}

Aucott, Timothy ^{[1
]}

Dauses, Tianna ^{[1
]}

Odchimar-Reissig, Rosalie ^{[5
]}

Licht, Jonathan ^{[6
]}

McConnell, Melanie J. ^{[7
]}

Nasrallah, Chris ^{[8
]}

Kim, Marianne K. H. ^{[6
]}

Zhang, Weijia ^{[9
]}

Sun, Yezou ^{[10
]}

Murgo, Anthony ^{[11
]}

Espinoza-Delgado, Igor ^{[11
]}

Oteiza, Katharine ^{[1
]}

Owoeye, Ibitayo ^{[1
]}

Silverman, Lewis R. ^{[5
]}

Gore, Steven D. ^{[1
]}

Carraway, Hetty E. ^{[1
]}

机构：

[1] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA

[2] Johns Hopkins Univ, Dept Epidemiol, Bloomberg Sch Publ Hlth, Baltimore, MD USA

[3] Johns Hopkins Univ, Dept Biostat, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA

[4] Univ So Calif, Norris Canc Ctr, Div Hematol, Los Angeles, CA USA

[5] Mt Sinai Med Ctr, Div Med Oncol, New York, NY 10029 USA

[6] Northwestern Univ, Feinberg Sch Med, Robert H Lurie Comprehens Canc Ctr, Div Hematol Oncol, Chicago, IL 60611 USA

[7] Malaghan Inst Med Res, Wellington, New Zealand

[8] Univ Calif Berkeley, Ctr Theoret Evolutionary Genet, Berkeley, CA 94720 USA

[9] Mt Sinai Sch Med, Div Hematol Oncol, New York, NY USA

[10] Mt Sinai Sch Med, Personalized Med Res Program, New York, NY USA

[11] NCI, Canc Therapy Evaluat Program, Rockville, MD USA

来源：

BLOOD | 2009年 / 114卷 / 13期

基金：

英国惠康基金;

关键词：

HISTONE DEACETYLASE INHIBITION; 5-AZA-2'-DEOXYCYTIDINE DECITABINE TREATMENT; MYELODYSPLASTIC SYNDROME; VALPROIC ACID; METHYLTRANSFERASE INHIBITORS; HEMATOPOIETIC MALIGNANCIES; HEMATOLOGIC MALIGNANCIES; METHYLATION STATUS; HUMAN CANCER; LEUKEMIA;

D O I：

10.1182/blood-2009-02-203547

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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 (p15(INK4B), 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 gamma-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. (Blood. 2009;114:2764-2773)

引用

页码：2764 / 2773

页数：10

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