TY - JOUR
T1 - 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
AU - Fandy, Tamer E.
AU - Herman, James G.
AU - Kerns, Patrick
AU - Jiemjit, Anchalee
AU - Sugar, Elizabeth A.
AU - Choi, Si Ho
AU - Yang, Allen S.
AU - Aucott, Timothy
AU - Dauses, Tianna
AU - Odchimar-Reissig, Rosalie
AU - Licht, Jonathan
AU - McConnell, Melanie J.
AU - Nasrallah, Chris
AU - Kim, Marianne K.H.
AU - Zhang, Weijia
AU - Sun, Yezou
AU - Murgo, Anthony
AU - Espinoza-Delgado, Igor
AU - Oteiza, Katharine
AU - Owoeye, Ibitayo
AU - Silverman, Lewis R.
AU - Gore, Steven D.
AU - Carraway, Hetty E.
PY - 2009
Y1 - 2009
N2 - 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.
AB - 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.
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U2 - 10.1182/blood-2009-02-203547
DO - 10.1182/blood-2009-02-203547
M3 - Article
C2 - 19546476
AN - SCOPUS:70350506791
SN - 0006-4971
VL - 114
SP - 2764
EP - 2773
JO - Blood
JF - Blood
IS - 13
ER -