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

Rozati, Sima; Cheng, Phil F.; Widmer, Daniel; Fujii, Kazuyasu; Levesque, Mitchell P.; Dummer, Reinhard

doi:10.1158/1078-0432.ccr-15-1435

Cited by 50 publications

(41 citation statements)

References 44 publications

(51 reference statements)

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“…Future studies should focus on DNA repair mechanisms in subpopulations of skin T cells from CTCL patients. Further, new data on chromatin‐modifying genes may help in a better understanding of the genotraumatic cells lying behind CTCL …”

Section: Resultsmentioning

confidence: 99%

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Cutaneous T‐Cell Lymphoma. A hypothesis on disease pathophysiology involving deficiency in DNA repair

Thestrup‐Pedersen

2016

Acad Dermatol Venereol

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Cutaneous T-cell lymphoma (CTCL) is a rare disease occurring in Europe among two persons per million per year. It affects men more often than women (2:1). It is primarily a skin disease. In about 20% of patients, it becomes fatal with tumours in the skin and spreading to lymph glands. Approximately 3% of patients show a leukemic form called Sezary's syndrome, where malignant cells are present in blood with accompanying erythrodermia. CTCL is a T-lymphocyte disease occurring late in life as the average age of patients is around 66 years in Europe, Japan and the US. This article focuses on cell lines and immune surveillance in CTCL, and especially the pronounced chromosomal instability. It leads to the hypothesis that chromosomal changes is the key event linked to DNA repair deficiencies, which in a subpopulation of T cells leads to CTCL development over years.

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Section: Resultsmentioning

confidence: 99%

“…Further, new data on chromatin-modifying genes may help in a better understanding of the genotraumatic cells lying behind CTCL. 32…”

Section: Resultsmentioning

confidence: 99%

Cutaneous T‐Cell Lymphoma. A hypothesis on disease pathophysiology involving deficiency in DNA repair

Thestrup‐Pedersen

2016

Acad Dermatol Venereol

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“…Despite FDA approval for CTCL, SAHA's exact mechanisms of action in CTCL are not clear. It inhibits histone deacetylases, resulting in the accumulation of acetylated histones important for the expression of genes including those that induce cell apoptosis and differentiation [21], [22]. IL-15 has been long known to be expressed by CTCL and to support CTCL proliferation and survival [23].…”

Section: Discussionmentioning

confidence: 99%

Preclinical Studies Support Combined Inhibition of BET Family Proteins and Histone Deacetylases as Epigenetic Therapy for Cutaneous T-Cell Lymphoma

et al. 2019

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Advanced-stage cutaneous T-cell lymphoma (CTCL) is usually a fatal malignancy despite optimal use of currently available treatments. In this preclinical study of novel CTCL therapy, we performed in vitro and ex vivo experiments to determine the efficacy of combination treatment with a panel of BET bromodomain inhibitors (BETi) (JQ1, OTX015, CPI-0610, I-BET762) and HDAC inhibitors (HDACi) (SAHA/Vorinostat, Romidepsin). BETi/HDACi combinations were synergistic (combination index <1) against cell viability and induced G0/G1 cell cycle arrest. Apoptosis was uniformly enhanced. From a mechanistic standpoint, proliferative drivers c-Myc, Cyclin D1, NFkB, and IL-15Rα were reduced. Inhibitory CDKN1A was increased. CDKN1B, IL-7R, IL-17Rα, STAT3, and STAT5 alterations varied. There were significant increases in extrinsic apoptotic pathway death receptors and ligands (FasL, DR4, DR5, TRAIL, and TNFR1). At clinically tolerable levels of single agents, Romidepsin (1 nM) + OTX015 (125 nM) induced the greatest apoptosis (60%_80%) at 96 hours. Ex vivo studies of leukemic CTCL cells obtained from patients with Sezary syndrome also showed higher levels of apoptosis (about 60%-90%) in response to combination treatments relative to single agents. In contrast, combination treatment of normal CD4+ T cells induced only minimal apoptosis (<10%). Our findings show that the mechanism of action of BETi/HDACi therapy in CTCL involves induction of both cell cycle arrest and apoptosis with reduced proliferative drivers and enhanced expression of apoptotic extrinsic pathway death receptors and ligands. Relative to single agents, the superior anti-CTCL effects of BETi/HDACi combinations in vitro and ex vivo provide a rationale for clinical trials exploring their efficacy as therapy for CTCL.

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“…9,10). Of note, CTCL demonstrates abnormal patterns of methylation and expression of tumor suppressor genes correlating with the clinical disease presentation (ref.…”

Section: Introductionmentioning

confidence: 99%

Decitabine Priming Enhances Mucin 1 Inhibition Mediated Disruption of Redox Homeostasis in Cutaneous T-Cell Lymphoma

Jain

Washington

Leaf

et al. 2017

Molecular Cancer Therapeutics

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Cutaneous T-cell lymphoma (CTCL) is a heterogeneous neoplasm and patients with relapsed/refractory disease exhibit resistance to standard therapies. We have previously demonstrated that the MUC1-C oncoprotein plays a critical role in protection from oxidative stress in CTCL cells. Targeting of MUC1-C with a pharmacologic inhibitor, GO-203, was associated with apoptosis in CTCL. However, disease responses were incomplete underscoring the need for combinatorial strategies that could exploit the vulnerability of CTCL cells to oxidative signals. Cell lines, primary samples and xenograft models of CTCL were used to assess synergy of GO-203 with decitabine, a hypomethylating agent. Present studies demonstrate that exposure of CTCL cells to decitabine in combination with GO-203, increased the generation of reactive oxygen species (ROS) levels and decreased levels of scavenger molecules, NADP, NADPH, glutathione (GSH), and TIGAR, critical to intracellular redox homeostasis. Dual exposure to GO-203 and decitabine resulted in marked down-regulation of DNA methyl transferases demonstrating significant synergy of these agents in inducing global and gene specific hypomethylation. Accordingly, treatment with decitabine and GO-203 upregulated the ROS generating enzymes, NADPH oxidase 4 (Nox4) and Dual oxidase 2 (Duox2) potentially due to their effect on epigenomic regulation of these proteins. In concert with these findings, exposure to decitabine and GO-203 resulted in heightened apoptotic death in CTCL cell lines, patient derived primary samples and in a murine xenograft model. These findings indicate that decitabine intensifies MUC1-C inhibition induced redox imbalance and provides a novel combination of targeted and epigenetic agents for patients with CTCL.

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

Cited by 50 publications

References 44 publications

Cutaneous T‐Cell Lymphoma. A hypothesis on disease pathophysiology involving deficiency in DNA repair

Cutaneous T‐Cell Lymphoma. A hypothesis on disease pathophysiology involving deficiency in DNA repair

Preclinical Studies Support Combined Inhibition of BET Family Proteins and Histone Deacetylases as Epigenetic Therapy for Cutaneous T-Cell Lymphoma

Decitabine Priming Enhances Mucin 1 Inhibition Mediated Disruption of Redox Homeostasis in Cutaneous T-Cell Lymphoma

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