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.
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.
Fandy
Tamer E
TE
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, USA.
Herman
James G
JG
Kerns
Patrick
P
Jiemjit
Anchalee
A
Sugar
Elizabeth A
EA
Choi
Si-Ho
SH
Yang
Allen S
AS
Aucott
Timothy
T
Dauses
Tianna
T
Odchimar-Reissig
Rosalie
R
Licht
Jonathan
J
McConnell
Melanie J
MJ
Nasrallah
Chris
C
Kim
Marianne K H
MK
Zhang
Weijia
W
Sun
Yezou
Y
Murgo
Anthony
A
Espinoza-Delgado
Igor
I
Oteiza
Katharine
K
Owoeye
Ibitayo
I
Silverman
Lewis R
LR
Gore
Steven D
SD
Carraway
Hetty E
HE
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
D001549:Benzamides; D011725:Pyridines; C118739:entinostat; D001374:Azacitidine