Combination treatment of acute myeloid leukemia cells with DNMT and HDAC inhibitors: predominant synergistic gene downregulation associated with gene body demethylation

Blagitko-Dorfs, Nadja; Schlosser, Pascal; Greve, Gabriele; Pfeifer, Dietmar; Meier, Ruth; Baude, Annika; Brocks, David; Plass, Christoph; Lübbert, Michael

doi:10.1038/s41375-018-0293-8

Cited by 76 publications

(54 citation statements)

References 52 publications

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“…As a single agent, decitabine treatment achieved a CR rate of 15-21% in patients with r/r AML [24,25]. Preclinical studies have shown that hypomethylating agents exhibit synergistic activity in leukemia cells when combined with an HDAC inhibitor [9,26,27]. Several clinical trials have explored the clinical benefit of a DNMT inhibitor in combination with an HDAC inhibitor for AML patients [28,29].…”

Section: Discussionmentioning

confidence: 99%

“…All patients in this study were treated with the CDCAG regimen (Fig. S4) over a 28-day cycle: chidamide (30 mg, twice per week, days [1][2][3][4][5][6][7][8][9][10][11][12][13][14] and decitabine (20 mg/m 2 /day, days 1-5) in combination with cytarabine (50 mg/m 2 /day, days 1-7 if WBC ≥ 20 × 10 9 /L and days 3-7 if WBC < 20 × 10 9 /L), aclarubicin (10 mg/m 2 / day, days 3-7), and granulocyte colony-stimulating factor (300 μg/day until WBC > 20 × 10 9 /L). Supportive treatment, including anti-infection prophylaxis and growth factor support, was allowed at the investigator's discretion.…”

Section: Patients and Study Designmentioning

confidence: 99%

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Chidamide, decitabine, cytarabine, aclarubicin, and granulocyte colony-stimulating factor (CDCAG) in patients with relapsed/refractory acute myeloid leukemia: a single-arm, phase 1/2 study

et al. 2020

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Background: Epigenetic mechanisms play an important role in the chemoresistance of acute myeloid leukemia (AML). The clinical response to epigenetic modifier-based chemotherapy in patients with relapsed/refractory AML (r/ r AML) is unclear. This multicenter clinical trial evaluated the safety and efficacy of epigenetic modifiers (chidamide and decitabine) in combination with aclarubicin, cytarabine, and granulocyte colony-stimulating factor (G-CSF) in patients with r/r AML. Results: Adult patients with r/r AML were treated with chidamide, decitabine, cytarabine, aclarubicin, and G-CSF (CDCAG). The primary measures were overall response (OR), overall survival (OS), and safety. Next-generation sequencing was performed to analyze the correlation between gene mutations and response. A total of 93 patients with r/r AML were enrolled. Overall, 24 patients had a complete remission (CR) and 19 patients achieved CR with incomplete blood count recovery (CRi). The overall response rate (ORR) was 46.2%. The overall survival of these 43 patients who achieved CR/CRi was significantly longer than that of patients who failed to achieve remission (563 vs 152 days, P < 0.0001). Of the patients with mutations in epigenetic and transcription factor-related genes, but without internal tandem duplications in FMS-like tyrosine kinase3 (FLT3-ITDs), 55.6% achieved CR/CRi, whereas the ORR was 28.2% for patients with mutations in other genes.

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Section: Discussionmentioning

confidence: 99%

Section: Patients and Study Designmentioning

confidence: 99%

Chidamide, decitabine, cytarabine, aclarubicin, and granulocyte colony-stimulating factor (CDCAG) in patients with relapsed/refractory acute myeloid leukemia: a single-arm, phase 1/2 study

et al. 2020

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“…Similarly, in both our study ( Figure 6E-H) and others, the combination of DAC with HDAC inhibitors is more efficacious due to the synergistic deregulation of specific cell-survival genes. 65,[71][72][73] Precise mechanisms responsible for this synergy remain to be elucidated and are likely to involve numerous signaling molecules 63,65,71,73,74 and to be cell type dependent. Our model suggests that these antimyeloma therapies upregulate TAZ, leading to decreased MYC expression and its transcriptional program and subsequent cell death.…”

Section: Discussionmentioning

confidence: 99%

TAZ functions as a tumor suppressor in multiple myeloma by downregulating MYC

et al. 2019

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“…5-azacytidine and 5-aza-2 -deoxycytidine (decitabine, DAC), a DNMT inhibitor, are used in the treatment in elderly patients with myelodysplastic syndromes (MDS) and AML [85]. Combinations of decitabine and HDAC inhibitors appeared logical, with pre-clinical synergistic effects on gene expression re-activation [86], but resulted in limited clinical efficacy in clinical trials [87].…”

Section: Retinoid Acid Signaling Pathway In Cancer and Leukemiamentioning

confidence: 99%

Retinoic Acid Receptors in Acute Myeloid Leukemia Therapy

Martino

Welch

2019

Cancers

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Retinoic acid (RA) signaling pathways regulate fundamental biological processes, such as cell proliferation, development, differentiation, and apoptosis. Retinoid receptors (RARs and RXRs) are ligand-dependent transcription factors. All-trans retinoic acid (ATRA) is the principal endogenous ligand for the retinoic acid receptor alpha (RARA) and is produced by the enzymatic oxidation of dietary vitamin A, whose deficiency is associated with several pathological conditions. Differentiation therapy using ATRA revolutionized the outcome of acute promyelocytic leukemia (APL), although attempts to replicate these results in other cancer types have been met with more modest results. A better knowledge of RA signaling in different leukemia contexts is required to improve initial designs. Here, we will review the RA signaling pathway in normal and malignant hematopoiesis, and will discuss the advantages and the limitations related to retinoid therapy in acute myeloid leukemia.

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Combination treatment of acute myeloid leukemia cells with DNMT and HDAC inhibitors: predominant synergistic gene downregulation associated with gene body demethylation

Cited by 76 publications

References 52 publications

Chidamide, decitabine, cytarabine, aclarubicin, and granulocyte colony-stimulating factor (CDCAG) in patients with relapsed/refractory acute myeloid leukemia: a single-arm, phase 1/2 study

Chidamide, decitabine, cytarabine, aclarubicin, and granulocyte colony-stimulating factor (CDCAG) in patients with relapsed/refractory acute myeloid leukemia: a single-arm, phase 1/2 study

TAZ functions as a tumor suppressor in multiple myeloma by downregulating MYC

Retinoic Acid Receptors in Acute Myeloid Leukemia Therapy

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