title: 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.
abstract: 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.
authors: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, USA.
authors: Tamer E
authors: TE
authors: Fandy
authors: James G
authors: JG
authors: Herman
authors: Patrick
authors: P
authors: Kerns
authors: Anchalee
authors: A
authors: Jiemjit
authors: Elizabeth A
authors: EA
authors: Sugar
authors: Si-Ho
authors: SH
authors: Choi
authors: Allen S
authors: AS
authors: Yang
authors: Timothy
authors: T
authors: Aucott
authors: Tianna
authors: T
authors: Dauses
authors: Rosalie
authors: R
authors: Odchimar-Reissig
authors: Jonathan
authors: J
authors: Licht
authors: Melanie J
authors: MJ
authors: McConnell
authors: Chris
authors: C
authors: Nasrallah
authors: Marianne K H
authors: MK
authors: Kim
authors: Weijia
authors: W
authors: Zhang
authors: Yezou
authors: Y
authors: Sun
authors: Anthony
authors: A
authors: Murgo
authors: Igor
authors: I
authors: Espinoza-Delgado
authors: Katharine
authors: K
authors: Oteiza
authors: Ibitayo
authors: I
authors: Owoeye
authors: Lewis R
authors: LR
authors: Silverman
authors: Steven D
authors: SD
authors: Gore
authors: Hetty E
authors: HE
authors: Carraway
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D001374:Azacitidine / Q000008:administration & dosage*; D001549:Benzamides / Q000008:administration & dosage*; D020732:Cytogenetic Analysis; D004249:DNA Damage / Q000187:drug effects* / Q000502:physiology; D004334:Drug Administration Schedule; D044127:Epigenesis, Genetic / Q000187:drug effects* / Q000502:physiology; D005260:Female; D019337:Hematologic Neoplasms / Q000175:diagnosis* / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011725:Pyridines / Q000008:administration & dosage*; D013997:Time Factors
chemical_list: D001549:Benzamides; D011725:Pyridines; C118739:entinostat; D001374:Azacitidine