A specific DNA methylation profile correlates with a high risk of disease progression in stage I classical (Alibert-Bazin type) mycosis fungoides

Ferrara, Gerardo; Pancione, Massimo; Votino, Carolina; Quaglino, Pietro; Tomasini, Carlo Francesco; Santucci, Marco; Pimpinelli, Nicola; Cusano, Francesco; Sabatino, Lina; Colantuoni, Vittorio

doi:10.1111/bjd.12717

Cited by 21 publications

(19 citation statements)

References 38 publications

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“…IC 50 of romidepsin was within the range of what was previously reported in preclinical studies (24). The calculated IC 50 of azacitidine varied between cell lines but remained mostly >5 mmol/L even after 48 hours of treatment (Fig. 1B).…”

Section: Romidepsin and Azacitidine Combination Treatment Synergize Isupporting

confidence: 84%

“…Nonetheless, the differentially methylated genes specific in the combination treatment underline the important contribution of demethylation to the synergistic effect. This profile might serve as the basis for the identification of a methylation signature that is predictive of clinical response as shown in myelodysplastic syndrome (49) or to a limited extent suggested recently in CTCL (50).…”

Section: Discussionmentioning

confidence: 94%

“…21; or half the maximal inhibitory concentration (IC 50 )] values for each cell line at different time points were determined using CompuSyn software (22) based on the quantitative analysis of dose-effect relationships on multiple drugs or enzyme inhibitors by Chou and Talalay (23). Combinational index (CI) values were calculated to confirm synergy.…”

Section: Discussionmentioning

confidence: 99%

“…1A). We determined the IC 50 for romidepsin and azacitidine in all cell lines (MyLa, SeAx, and Hut78) at 24 and 48-hour time point utilizing the CompuSyn software. IC 50 of romidepsin was within the range of what was previously reported in preclinical studies (24).…”

Section: Romidepsin and Azacitidine Combination Treatment Synergize Imentioning

confidence: 99%

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Romidepsin and Azacitidine Synergize in their Epigenetic Modulatory Effects to Induce Apoptosis in CTCL

Rozati

Cheng

Widmer

et al. 2016

Clinical Cancer Research

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Purpose: Cutaneous T-cell lymphomas (CTCL) are a heterogeneous group of malignancies that despite available therapies commonly relapse. The emergence of combination epigenetic therapies in other hematologic malignancies have made investigation of such combinations in CTCL a priority. Here, we explore the synergistic antiproliferative effects of romidepsin, an HDAC inhibitor, and azacitidine, a demethylating agent, combination in CTCL.Experimental Design: The growth inhibition under combination treatment and single agent was explored by the MTT cell viability assay and the Annexin V/propidium iodide (PI) apoptosis assay in different CTCL cell lines and tumor cells derived from S ezary syndrome patients. Quantitative analysis of a dose-effect relationship of romidepsin and azacitidine was done by the CompuSyn software. Investigation of mechanism of action was performed by flow cytometry, immunoblotting, qRT-PCR arrays, and chromatin immunoprecipitation. Global CpG methylation sequencing was utilized to study genome methylation alteration under the treatment modalities.Results: The combination of romidepsin and azacitidine exerts synergistic antiproliferative effects and induction of apoptosis involving activation of the caspase cascade in CTCL cell lines and tumor cells derived from S ezary syndrome patients. We identified genes that were selectively induced by the combination treatment, such as the tumor suppressor gene RhoB that is linked to enhanced histone acetylation at its promoter region in parallel with pronounced expression of p21. Global CpG methylation sequencing in a CTCL cell line and tumor cells demonstrated a subset of genes with a unique change in methylation profile in the combination treatment.Conclusions: The synergistic antiproliferative effects of romidepsin and azacitidine combination treatment justify further exploration in clinical trials for advanced CTCL.

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Section: Romidepsin and Azacitidine Combination Treatment Synergize Isupporting

confidence: 84%

Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Section: Romidepsin and Azacitidine Combination Treatment Synergize Imentioning

confidence: 99%

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Romidepsin and Azacitidine Synergize in their Epigenetic Modulatory Effects to Induce Apoptosis in CTCL

Rozati

Cheng

Widmer

et al. 2016

Clinical Cancer Research

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“…30 Furthermore, there is evidence for different methylation patterns and gene expression profiles in higher stage CTCL. 31,32 Although dramatic reductions in T-cell counts were observed by day 4 or 5 in 70% of evaluable patients, only seven patients had EBV and CMV viremia. Only a single patient (#29) had a clinical EBV infection with liver failure, renal failure and metabolic acidosis.…”

mentioning

confidence: 99%

Resimmune, an anti-CD3 recombinant immunotoxin, induces durable remissions in patients with cutaneous T-cell lymphoma

et al. 2015

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Resimmune is a second-generation recombinant immunotoxin composed of the catalytic and translocation domains of diphtheria toxin fused to two single chain antibody fragments reactive with the extracellular domain of CD3ε. We gave intravenous infusions of Resimmune 2.5 -11.25 μg/kg over 15 minutes to 30 patients (25 with cutaneous T-cell lymphoma, 3 with peripheral T-cell lymphoma, 1 with T-cell large granular lymphocytic leukemia and 1 with T-cell prolymphocytic leukemia) in an inter-patient dose escalation trial. The most common adverse events were fever, chills, hypotension, edema, hypoalbuminemia, hypophosphatemia, and transaminasemia. Among the 25 patients with cutaneous T-cell lymphoma, there were nine responses for a response rate of 36% (95% CI, 18%-57%) including four complete remissions (16%, 95% CI, 5%-36%). The durations of the complete remissions were 72+, 72+, 60+ and 38+ months. There were five partial remissions lasting 3, 3, 3+, 6+ and 14 months. Of 17 patients with a modified skin weighted assessment tool score <50, 17 patients with stage IB/IIB, and 11 patients with both a score <50 and stage IB/IIB, nine (53%), eight (47%), and eight (73%) had responses, respectively. Further studies of Resimmune in patients with low tumor burden, stage IB-IIB cutaneous T-cell lymphoma are warranted. This trial is registered at clinicaltrials.gov as #NCT00611208. Resimmune, an anti-CD3ε recombinant immunotoxin, induces durable remissions in patients with cutaneous T-cell lymphoma ABSTRACT MethodsThe Resimmune study was a single-arm, multicenter interpatient dose escalation phase 1 trial in patients with advanced CD3 + T-cell malignancies. The study was performed under the sponsorship of Angimmune, LLC, registered at clinical trials.gov as NCT00611208, and approved by Institutional Review Boards at the participating institutions. Thirty patients were treated with a single course of Resimmune at doses ranging from 2.5 to 11.25 μg/kg intravenously twice daily for 4 days. Eligibility and diagnosisPatients with CD3 + T-cell malignancies, diagnosed by morphological, histochemical, and cell surface criteria, in whom systemic therapy had failed were eligible for the study.

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Mycosis fungoides

2020

Skin Lymphoma

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A specific DNA methylation profile correlates with a high risk of disease progression in stage I classical (Alibert-Bazin type) mycosis fungoides

Abstract: Epigenetic silencing of specific biomarkers can predict the risk of disease progression in early-stage MF, providing insights into its pathogenesis, prognosis and therapy.

Cited by 21 publications

References 38 publications

Romidepsin and Azacitidine Synergize in their Epigenetic Modulatory Effects to Induce Apoptosis in CTCL

Romidepsin and Azacitidine Synergize in their Epigenetic Modulatory Effects to Induce Apoptosis in CTCL

Resimmune, an anti-CD3 recombinant immunotoxin, induces durable remissions in patients with cutaneous T-cell lymphoma

Mycosis fungoides

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