Combining DNA methyltransferase and histone deacetylase inhibition to treat acute myeloid leukemia/myelodysplastic syndrome: Achievements and challenges

Abstract

Already in 1982, shortly after the discovery of 5-azacytidine (5-aza) and 5-aza-2 0 -deoxycytidine (decitabine [DAC]) as powerful DNA-hypomethylating agents, Jahangeer and colleagues reported that treatment of HeLa cells with 5-aza followed by butyrate, a histone deacetylase (HDAC) inhibitor, induced b-adrenergic receptor expression in a synergistic fashion.1 This probably first report of combination treatment with 2 chromatin-modifying agents, was followed by many other in vitro studies combining the DNA methyltransferase (Dnmt) inhibitors 5-aza and DAC with different HDAC inhibitors to enhance their antineoplastic potency.2,3 For instance, as reported in a landmark article by Cameron et al,4 who applied sequential treatment with DAC and trichostatin A, several cell cycle-associated genes that are epigenetically silenced in colorectal cancer and acute myeloid leukemia (AML) cells were induced synergistically by this combination, providing a rationale for clinical trials using this approach.The azanucleoside drugs 5-aza and DAC have recently become the new therapeutic standard in the treatment of different types of AML and myelodysplastic syndrome (MDS) 5-7 because of their ability to induce objective remissions and prolong overall survival compared with low-dose cytarabine or sole best supportive care, even in patients with adverse cytogenetics. However, not all patients are responsive to Dnmt inhibitors; therefore, it is a very pertinent question whether the combination of these drugs with HDAC inhibitors with proven activity in myeloid neoplasias might further improve response rates these patients and prolong time to treatment resistance.Several different HDAC inhibitors have entered the clinical arena; they belong to different chemical classes and, in vitro and in vivo, can be differentiated by their abilities to inhibit enzymes that belong to both class I and II HDACs (socalled pan-HDAC inhibitors) or are class-selective (for review, see Wagner et al 8 ). Valproic acid (VPA) is an orally available, short-chain fatty acid-based pan-HDAC inhibitor that has single-agent activity particularly in patients with MDS who have lower-risk features.9,10 It has also been combined safely with DAC or 5-aza in AML/MDS patients, but so far only in single-arm studies (shown in Table 1), [11][12][13][14][15][16] in which it appeared to shorten the time to complete remission compared with historic data from the Dnmt inhibitor given alone. Therefore, the current study by Issa and colleagues 17 in this issue of Cancer provides the first randomized clinical trial addressing the value of oral VPA for 7 days as an add-on to DAC started concurrently with 5 daily infusions (20 mg/m 2 ) of the Dnmt inhibitor. The authors enrolled 149 older patients with AML or high-risk MDS in their study and also included patients with proliferative disease (ie, leukocytosis) who were first cytoreduced with hydroxyurea. Adaptive randomization was used to assign 70 patients (the majority with AML) to a DAC-alone arm and 79 patients (the majority wi...

A phase 1b/2b multicenter study of oral panobinostat plus azacitidine in adults with MDS, CMML or AML with ⩽30% blasts

“…Similar results were found in phase 2 studies of vorinostat+AZA for higher-risk MDS and CMML, 21 entinostat+AZA for MDS and AML, 22 pracinostat+AZA for previously untreated MDS, 23 and valproic acid+decitabine for MDS and AML. 24 , 25 , 26 …”

Knockdown of SALL4 Protein Enhances All-trans Retinoic Acid-induced Cellular Differentiation in Acute Myeloid Leukemia Cells

“…However, when the cells were cotreated with Dox to induce SALL4 overexpression, these ATRA effects were largely blocked, as demonstrated by substantially increased cell survival and reduced irregular cell appearance under the microscope. We then performed flow cytometry assays using CD11b and CD14 myeloid differentiation markers to quantify the observed blocking effect (22). SALL4 overexpression reversed the ATRA-induced differentiation by up to ϳ60 -70%, and this effect was also corelated with the SALL4 overexpression levels (Fig.…”

Selective Inhibitors of Histone Deacetylases 1 and 2 Synergize with Azacitidine in Acute Myeloid Leukemia

“…HDAC inhibitors have also shown promising clinical activity in combination with agents with known anti-leukemia activity, including DNA methyltransferase inhibitors and chemotherapies, in AML patients [2, 28–36]. However, adding non-selective HDAC inhibitors to combination regimens often results in increased toxicities which can lead to dose reduction and early treatment discontinuation [33, 36–45]. Therefore, isozyme-selective HDAC inhibitors with improved safety profiles may overcome this hurdle and provide additional clinical benefit to patients.…”