Clinical development of demethylating agents in hematology

Navada, Shyamala C.; Steinmann, Juliane; Lübbert, Michael; Silverman, Lewis R.

doi:10.1172/jci69739

Cited by 133 publications

(115 citation statements)

References 62 publications

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“…Some studies suggest that treatment with hypomethylating agents should precede treatment with HDAC inhibitors for optimum synergy (12,28). Therefore, based on the in vitro experiments and preliminary experiments on tumor cells derived from S ezary syndrome patients that were treated with different concentration of romidepsin and/or azacitidine (data not shown), optimum antiproliferative effects were reached with azacitidine 2.5 mmol/L for 4 days and romidepsin 2.5 nmol/L was added for the last 24 hours.…”

Section: Romidepsin and Azacitidine Combination Treatment Synergize Imentioning

confidence: 99%

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 Imentioning

confidence: 99%

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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“…Although known to demethylate DNA, the link between demethylation-induced transcription and the therapeutic effects of these drugs is not well established (21). On one hand, demethylation can re-activate tumor suppressors that were repressed by promoter methylation, resulting in tumor suppressor-induced cancer cell death (22). On the other hand, demethylation of CpG loci within gene bodies can paradoxically decrease gene transcription (23).…”

Section: Introductionmentioning

confidence: 99%

Demethylation Therapy as a Targeted Treatment for Human Papillomavirus–Associated Head and Neck Cancer

Biktasova

Hajek

Sewell

et al. 2017

Clinical Cancer Research

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Purpose: DNA methylation in human papillomavirus-associated (HPV þ ) head and neck squamous cell carcinoma (HNSCC) may have importance for continuous expression of HPV oncogenes, tumor cell proliferation, and survival. Here, we determined activity of a global DNA-demethylating agent, 5-azacytidine (5-aza), against HPV þ HNSCC in preclinical models and explored it as a targeted therapy in a window trial enrolling patients with HPV þ HNSCC.Experimental Design: Sensitivity of HNSCC cells to 5-aza treatment was determined, and then 5-aza activity was tested in vivo using xenografted tumors in a mouse model. Finally, tumor samples from patients enrolled in a window clinical trial were analyzed to identify activity of 5-aza therapy in patients with HPV þ HNSCC.Results: Clinical trial and experimental data show that 5-aza induced growth inhibition and cell death in HPV þ HNSCC. classically associated with tobacco and alcohol exposure, including loss-of-function mutations of TP53 (84%) and loss or inactivating mutations of CDKN2A (54%). In contrast, genetic alterations in these genes are extremely rare in the HPV þ subset (TP53, 3%; CDKN2A, 0%; ref. 6), which instead is associated with a mutational signature typical of apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 (APOBEC3) antiviral proteins (6, 11-13). In addition, The Cancer Genome Atlas (TCGA) head and neck study found that TNF receptor-associated factor 3 (TRAF3) and CYLD genes are commonly mutated and deleted in HPV þ HNSCC (6,8,14). Finally, HPV À HNSCC have relatively low levels of DNA methylation, which is correlated with genomic instability (15), whereas HPV þ HNSCC harbor distinctly hypermethylated genomes (7,8,16,17). Demographic, clinical, molecular, and epigenetic differences between HPV þ and HPV À HNSCC suggest two distinct cancers, yet HPV À status is currently only used for prognosis and not to guide treatment (18). A majority of HNSCC patients are treated with radiation and platin-based chemotherapy, which is associated with deleterious and lifelong side-effects. Despite the relatively good prognosis associated with HPV þ HNSCC, 25%-30% of patients with HPV-positive tumors experience recurrent or metastatic disease, for which treatment options are limited. The molecular and epigenetic differences between HPV þ and HPV À tumors provide an opportunity for therapies that exploit the interaction of the HPV genome and host that result in hypermethylation of cancer cell genomes. 5-Azacytidine (5-aza)

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“…13) or chromatin remodeling (HDAC inhibitors or demethylating agents; refs. 14,15). Although these compounds have already entered clinical trials, the mechanisms by which they disturb transcription as well as those driving to cancer cell death are far from being understood.…”

Section: Introductionmentioning

confidence: 99%

Lurbinectedin Specifically Triggers the Degradation of Phosphorylated RNA Polymerase II and the Formation of DNA Breaks in Cancer Cells

Núñez

Robles

Giraudon

et al. 2016

Molecular Cancer Therapeutics

128

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We have defined the mechanism of action of lurbinectedin, a marine-derived drug exhibiting a potent antitumor activity across several cancer cell lines and tumor xenografts. This drug, currently undergoing clinical evaluation in ovarian, breast, and small cell lung cancer patients, inhibits the transcription process through (i) its binding to CG-rich sequences, mainly located around promoters of protein-coding genes; (ii) the irreversible stalling of elongating RNA polymerase II (Pol II) on the DNA template and its specific degradation by the ubiquitin/proteasome machinery; and (iii) the generation of DNA breaks and subsequent apoptosis. The finding that inhibition of Pol II phosphorylation prevents its degradation and the formation of DNA breaks after drug treatment underscores the connection between transcription elongation and DNA repair. Our results not only help to better understand the high specificity of this drug in cancer therapy but also improve our understanding of an important transcription regulation mechanism. Mol Cancer Ther; 15(10); 2399-412. Ó2016 AACR.

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Clinical development of demethylating agents in hematology

Cited by 133 publications

References 62 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

Demethylation Therapy as a Targeted Treatment for Human Papillomavirus–Associated Head and Neck Cancer

Lurbinectedin Specifically Triggers the Degradation of Phosphorylated RNA Polymerase II and the Formation of DNA Breaks in Cancer Cells

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