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American Journal of Hematology May 2022Survival outcomes for relapsed/refractory pediatric acute myeloid leukemia (R/R AML) remain dismal. Epigenetic changes can result in gene expression alterations which...
Decitabine and vorinostat with FLAG chemotherapy in pediatric relapsed/refractory AML: Report from the therapeutic advances in childhood leukemia and lymphoma (TACL) consortium.
Survival outcomes for relapsed/refractory pediatric acute myeloid leukemia (R/R AML) remain dismal. Epigenetic changes can result in gene expression alterations which are thought to contribute to both leukemogenesis and chemotherapy resistance. We report results from a phase I trial with a dose expansion cohort investigating decitabine and vorinostat in combination with fludarabine, cytarabine, and G-CSF (FLAG) in pediatric patients with R/R AML [NCT02412475]. Thirty-seven patients enrolled with a median age at enrollment of 8.4 (range, 1-20) years. There were no dose limiting toxicities among the enrolled patients, including two patients with Down syndrome. The recommended phase 2 dose of decitabine in combination with vorinostat and FLAG was 10 mg/m . The expanded cohort design allowed for an efficacy evaluation and the overall response rate among 35 evaluable patients was 54% (16 complete response (CR) and 3 complete response with incomplete hematologic recovery (CRi)). Ninety percent of responders achieved minimal residual disease (MRD) negativity (<0.1%) by centralized flow cytometry and 84% (n = 16) successfully proceeded to hematopoietic stem cell transplant. Two-year overall survival was 75.6% [95%CI: 47.3%, 90.1%] for MRD-negative patients vs. 17.9% [95%CI: 4.4%, 38.8%] for those with residual disease (p < .001). Twelve subjects (34%) had known epigenetic alterations with 8 (67%) achieving a CR, 7 (88%) of whom were MRD negative. Correlative pharmacodynamics demonstrated the biologic activity of decitabine and vorinostat and identified specific gene enrichment signatures in nonresponding patients. Overall, this therapy was well-tolerated, biologically active, and effective in pediatric patients with R/R AML, particularly those with epigenetic alterations.
Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Cytarabine; Decitabine; Humans; Leukemia, Myeloid, Acute; Lymphoma; Vorinostat
PubMed: 35180323
DOI: 10.1002/ajh.26510 -
Blood Apr 2023Two articles in this week’s issue focus on the use of ipilimumab and decitabine for patients with myelodysplasia (MDS) and acute myeloid leukemia (AML) before and...
Two articles in this week’s issue focus on the use of ipilimumab and decitabine for patients with myelodysplasia (MDS) and acute myeloid leukemia (AML) before and after hematopoietic stem cell transplantation (HSCT) for high-risk disease. In the first article, Garcia et al report on the results of a phase 1 trial of the combination in 54 patients, demonstrating overall response rate of 52% in patients who are HSCT-naïve and 20% in patients post-HSCT; responses are usually short-lived. In the second article, Penter and colleagues characterize gene expression responses to therapy and conclude that decitabine acts directly to clear leukemic cells while ipilimumab acts on infiltrating lymphocytes in marrow and extramedullary sites. Responses are determined by leukemic cell burden and by the frequency and phenotype of infiltrating lymphocytes. Increasing bone marrow regulatory T cells is identified as a potential contributor to checkpoint inhibitor escape.
Topics: Humans; Decitabine; Ipilimumab; Myelodysplastic Syndromes; Azacitidine; Leukemia, Myeloid, Acute
PubMed: 36332187
DOI: 10.1182/blood.2022017686 -
The Journal of International Medical... Jul 2022Combination therapy has become the hallmark of lung cancer treatment, as it reduces the dosage intensity of individual drugs while increasing their efficacy. In the...
OBJECTIVE
Combination therapy has become the hallmark of lung cancer treatment, as it reduces the dosage intensity of individual drugs while increasing their efficacy. In the current study, we analyzed the combinatorial effect of decitabine and aspirin on non-small cell lung cancer (NSCLC) cell growth.
METHODS
In this study, we investigated the combinatorial effect of decitabine and aspirin by MTT, colony formation, and Transwell assays. We also explored the underlying molecular mechanism a series of and experiments.
RESULTS
The combination of decitabine and aspirin regulated cell viability and migration . Moreover, the combination therapy suppressed tumor cell growth by inhibiting the β-catenin/STAT3 signaling pathway. Our study also found that the regimen increased the phosphorylation of β-catenin and decreased the expression of STAT3 and β-catenin.
CONCLUSION
The combined administration of decitabine and aspirin significantly reduced tumor growth compared with single-agent treatment and the control . The study results indicated that decitabine and aspirin could suppress NSCLC cell growth and metastasis the β-catenin/STAT3 signaling pathway.
Topics: Aspirin; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Movement; Cell Proliferation; Decitabine; Humans; Lung Neoplasms; Wnt Signaling Pathway; beta Catenin
PubMed: 35869624
DOI: 10.1177/03000605221112024 -
Clinical Epigenetics Dec 2022The role of JAM3 in different tumors is controversial. The epigenetic regulation and the mechanism of JAM3 remain to be elucidated in human esophageal cancer (EC).
BACKGROUND
The role of JAM3 in different tumors is controversial. The epigenetic regulation and the mechanism of JAM3 remain to be elucidated in human esophageal cancer (EC).
METHODS
Eleven EC cell lines, 49 cases of esophageal intraepithelial neoplasia (EIN) and 760 cases of primary EC samples were employed. Methylation-specific polymerase chain reaction, immunohistochemistry, MTT, western blot and xenograft mouse models were applied in this study.
RESULTS
The inverse association between RNA expression and promoter region methylation of JAM3 was found by analyzing 185 cases of EC samples extracted from the TCGA database (p < 0.05). JAM3 was highly expressed in KYSE450, KYSE520, TE1 and YES2 cells, low level expressed in KYSE70 cells and unexpressed in KYSE30, KYSE150, KYSE410, KYSE510, TE13 and BIC1 cells. JAM3 was unmethylated in KYSE450, KYSE520, TE1 and YES2 cells, partial methylated in KYSE70 cells and completely methylated in KYSE30, KYSE150, KYSE410, KYSE510, TE13 and BIC1 cells. The expression of JAM3 is correlated with methylation status. The levels of JAM3 were unchanged in KYSE450, KYSE520, TE1 and YES2 cells, increased in KYSE70 cells and restored expression in KYSE30, KYSE150, KYSE410, KYSE510, TE13 and BIC1 cells after 5-aza-2'-deoxycytidine treatment, suggesting that the expression of JAM3 is regulated by promoter region methylation. JAM3 was methylated in 26.5% (13/49) of EIN and 51.1% (388/760) of primary EC, and methylation of JAM3 was associated significantly with tumor differentiation and family history (all p < 0.05). Methylation of JAM3 is an independent prognostic factor of poor 5-year overall survival (p < 0.05). JAM3 suppresses cell proliferation, colony formation, migration and invasion and induces G1/S arrest and apoptosis in EC. Further study demonstrated that JAM3 suppressed EC cells and xenograft tumor growth by inhibiting Wnt/β-catenin signaling.
CONCLUSION
JAM3 is frequently methylated in human EC, and the expression of JAM3 is regulated by promoter region methylation. JAM3 methylation is an early detection and prognostic marker of EC. JAM3 suppresses EC growth both in vitro and in vivo by inhibiting Wnt signaling.
Topics: Animals; Humans; Mice; Cell Adhesion Molecules; Decitabine; DNA Methylation; Epigenesis, Genetic; Esophageal Neoplasms; Immunoglobulins; Protein Processing, Post-Translational; Wnt Signaling Pathway
PubMed: 36461092
DOI: 10.1186/s13148-022-01388-3 -
Molecules (Basel, Switzerland) Mar 2022DNA methylation, as one of the major means of epigenesis change, makes a large difference in the spatial structure of chromatin, transposable element activity and,... (Review)
Review
DNA methylation, as one of the major means of epigenesis change, makes a large difference in the spatial structure of chromatin, transposable element activity and, fundamentally, gene transcription. It has been confirmed that DNA methylation is closely related to innate immune responses. Decitabine, the most efficient available DNA methyltransferase inhibitor, has demonstrated exhilarating immune activation and antiviral effects on multiple viruses, including HIV, HBV, HCV, HPV and EHV1. This review considers the role of decitabine in regulating innate immune responses and antiviral ability. Understanding the complex transcriptional and immune regulation of decitabine could help to identify and validate therapeutic methods to reduce pathogen infection-associated morbidity, especially virus infection-induced morbidity and mortality.
Topics: Antiviral Agents; Cognition; Decitabine; Immunity, Innate; Immunomodulation
PubMed: 35335337
DOI: 10.3390/molecules27061973 -
Cell Reports Sep 2023Decitabine (DAC) is clinically used to treat myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Our genome-wide CRISPR-dCas9 activation screen using...
Decitabine (DAC) is clinically used to treat myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Our genome-wide CRISPR-dCas9 activation screen using MDS-derived AML cells indicates that mitotic regulation is critical for DAC resistance. DAC strongly induces abnormal mitosis (abscission failure or tripolar mitosis) in human myeloid tumors at clinical concentrations, especially in those with TP53 mutations or antecedent hematological disorders. This DAC-induced mitotic disruption and apoptosis are significantly attenuated in DNMT1-depleted cells. In contrast, overexpression of Dnmt1, but not the catalytically inactive mutant, enhances DAC-induced mitotic defects in myeloid tumors. We also demonstrate that DAC-induced mitotic disruption is enhanced by pharmacological inhibition of the ATR-CLSPN-CHK1 pathway. These data challenge the current assumption that DAC inhibits leukemogenesis through DNMT1 inhibition and subsequent DNA hypomethylation and highlight the potent activity of DAC to disrupt mitosis through aberrant DNMT1-DNA covalent bonds.
Topics: Humans; Decitabine; Azacitidine; Antimetabolites, Antineoplastic; Leukemia, Myeloid, Acute; DNA Methylation; DNA; Adaptor Proteins, Signal Transducing
PubMed: 37714156
DOI: 10.1016/j.celrep.2023.113098 -
Blood Advances Apr 2021Since the US Food and Drug Administration (FDA) approvals of parenteral decitabine and azacitidine, DNA methyltransferase inhibitors, otherwise referred to as DNA... (Review)
Review
Since the US Food and Drug Administration (FDA) approvals of parenteral decitabine and azacitidine, DNA methyltransferase inhibitors, otherwise referred to as DNA hypomethylating agents (HMAs), have been a mainstay in the treatment of higher-risk myelodysplastic syndromes. The development of oral HMAs has been an area of active interest; however, oral bioavailability has been quite poor due to rapid metabolism by cytidine deaminase (CDA). This led to the development of the novel CDA inhibitor cedazuridine, which was combined with an oral formulation of decitabine. Preclinical work demonstrated a pharmacokinetic and pharmacodynamic profile approximate to parenteral decitabine, leading to early-phase clinical trials of oral cedazuridine-decitabine (C-DEC) in myelodysplastic syndromes and chronic myelomonocytic leukemia (CMML). A combination of oral decitabine 35 mg with oral cedazuridine 100 mg was established as the recommended phase 2 dose. Phase 2 data confirmed bioequivalence of C-DEC when compared with parenteral decitabine, and a larger phase 3 trial has demonstrated similar results, leading to the FDA approval of C-DEC for use in intermediate/high-risk myelodysplastic syndrome (MDS) and CMML. This review will focus upon the current role of HMA therapy in MDS/CMML, preclinical and clinical development of C-DEC, and potential roles of oral HMA therapy in myeloid malignancies moving forward.
Topics: Azacitidine; Decitabine; Humans; Leukemia, Myelomonocytic, Chronic; Myelodysplastic Syndromes; Uridine
PubMed: 33904891
DOI: 10.1182/bloodadvances.2020002929 -
Blood Feb 2013The ability of the DNA methyltransferase inhibitors (DNMTi) to induce terminal differentiation in fibroblasts was first noted by Taylor and Jones in 1979; Silverman and...
The ability of the DNA methyltransferase inhibitors (DNMTi) to induce terminal differentiation in fibroblasts was first noted by Taylor and Jones in 1979; Silverman and Holland reported hematologic improvement in patients with myelodysplastic syndrome (MDS) in 1993. That azacitidine improves survival in patients with high-risk MDS and acute myeloid leukemia with MDS features compared with a combined comparator group of supportive care, low-dose cytarabine, and intensive cytarabine plus anthracycline, while inducing trilineage normalization in approximately 15% of patients makes the development of more potent, more specific drugs that behave like azacitidine imperative. The question is, how do the azanucleosides behave?
Topics: Animals; Azacitidine; Decitabine; Gene Expression Regulation, Leukemic; Humans; Leukemia, Myeloid, Acute
PubMed: 23449614
DOI: 10.1182/blood-2013-02-483735 -
International Journal of Cancer May 2023To reduce the risk of relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT), there have been continuing efforts to optimize the conditioning...
Cladribine- and decitabine-containing conditioning regimen has a low post-transplant relapse rate in patients with relapsed or refractory acute myeloid leukemia and high-risk myelodysplastic syndrome.
To reduce the risk of relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT), there have been continuing efforts to optimize the conditioning regimens. Our study aimed to analyze the risk factors associated with the relapse of relapsed/refractory (R/R), high-risk acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS) post-transplant and the efficacy of a new conditioning regimen involving decitabine and cladribine. Clinical data of 125 patients with R/R AML, high-risk AML and high-risk MDS who underwent allo-HSCT were collected. In addition, 35 patients with R/R AML, high-risk AML and high-risk MDS received treatment with a new conditioning regimen including decitabine and cladribine. Cox regression analysis was used to identify risk factors associated with OS, RFS and relapse. Among 125 patients who underwent allo-HSCT, CR before allo-HSCT and matched sibling donors were independent protective factors for OS. DNMT3A abnormality was an independent risk factor for both relapse and RFS. Among 35 patients who received a new conditioning regimen containing decitabine and cladribine, only six patients relapsed and 1-year cumulative incidence of relapse was 11.7%. Moreover, this new regimen showed efficient MRD clearance early after allo-HSCT. The combined decitabine- and cladribine-based conditioning regimen showed a low relapse rate and a high survival without an increased incidence of GVHD or adverse effects and thus has potential for use in allo-HSCT for R/R AML, high-risk AML and high-risk MDS.
Topics: Humans; Cladribine; Decitabine; Graft vs Host Disease; Leukemia, Myeloid, Acute; Chronic Disease; Recurrence; Myelodysplastic Syndromes; Hematopoietic Stem Cell Transplantation; Retrospective Studies
PubMed: 36594582
DOI: 10.1002/ijc.34419 -
Endocrine-related Cancer Jun 2023Anaplastic thyroid cancer (ATC) is one of the most aggressive solid cancers in humans, with limited treatment options. Recent studies suggest that cancer stem cell (CSC)...
Anaplastic thyroid cancer (ATC) is one of the most aggressive solid cancers in humans, with limited treatment options. Recent studies suggest that cancer stem cell (CSC) activity contributes to therapeutic resistance and recurrence of ATC. We show that the expression of the endogenous thyroid hormone receptor β gene (THRB) is silenced in ATC and demonstrate that the exogenously expressed TRβ suppresses CSC activity. Decitabine is one of the demethylation agents to treat myelodysplastic syndrome and acute myeloid leukemia patients and is currently in clinical trials for hematopoietic malignancies and solid tumors. We aim to show that the re-expression of the endogenous THRB gene by decitabine can attenuate CSC activity to block ATC tumor growth. We treated ATC cell lines derived from human ATC tumors (11T and 16T cells) with decitabine and evaluated the effects of the reactivated endogenous TRβ on CSC activity in vitro and in vivo xenograft models. We found that treatment of 11T and 16T cells with decitabine reactivated the expression of endogenous TRβ, as evidenced by western blot and immunohistochemical analyses. The expressed TRβ inhibited cell proliferation by arresting cells at the S phase, increased apoptotic cell death by upregulation of cleaved caspase-3, and markedly suppressed the expression of CSC regulators, including cMYC, ALDH, SOX2, CD44, and β-catenin. Decitabine also inhibited xenograft tumor growth by suppressing CSC activity, inhibiting cancer cell proliferation, and increasing apoptosis. Our findings suggest that re-expression of the endogenous TRβ is a novel therapeutic approach for ATC via suppression of CSC activity.
Topics: Humans; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Thyroid Hormone Receptors beta; Genes, erbA; Decitabine; Cell Line, Tumor; Neoplastic Stem Cells; Apoptosis; Cell Proliferation
PubMed: 36939877
DOI: 10.1530/ERC-22-0306