Belinostat in patients with refractory or relapsed peripheral T-cell lymphoma: a perspective review

Sawas, Ahmed; Radeski, Dejan; O’Connor, Owen A.

doi:10.1177/2040620715592567

Cited by 91 publications

(56 citation statements)

References 27 publications

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“…Mocetinostat‐related AEs were primarily associated with fatigue, gastrointestinal disorders, weight loss and myelosuppression. This is consistent with the safety profiles observed with mocetinostat in other settings, and the safety profiles of other HDAC inhibitors (Garcia‐Manero et al , ; Blum et al , ; Younes et al , ; Foss et al , ; Ogura et al , ; Sawas et al , ). Additionally, four patients reported 5 pericardial events that were considered related to mocetinostat (pericardial effusion n = 3; pericarditis n = 1, cardiac tamponade n = 1).…”

Section: Discussionsupporting

confidence: 86%

A phase 2 study of mocetinostat, a histone deacetylase inhibitor, in relapsed or refractory lymphoma

et al. 2017

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Summary Deregulation of histone deacetylase (HDAC) is important in the pathogenesis of follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). Mocetinostat, an isotype-selective HDAC inhibitor, induces accumulation of acetylated histones, cell cycle arrest and apoptosis in several cancers. This phase 2 study evaluated mocetinostat in patients with relapsed/refractory (R/R) DLBCL and FL. Seventy-two patients received mocetinostat (starting doses: 70–110 mg TIW, 4-week cycles). The best overall response rate (95% CI) was 18.9% (7.2, 32.2) for the DLBCL cohort (n = 41), and 11.5% (1.7, 20.7) for the FL cohort (n = 31). Responses were durable (≥90 days in 7 of 10 responses). Overall, 54.1% and 73.1% of patients derived clinical benefit (response or stable disease) from mocetinostat in the DLBCL and FL cohorts, respectively. Progression-free survival ranged from 1.8 to 22.8 months and 11.8 to 26.3 months in responders with DLBCL and FL, respectively. The most frequent treatment-related adverse events were fatigue (75.0%), nausea (69.4%) and diarrhoea (61.1%). Although mocetinostat had limited single-agent activity in R/R DLBCL and FL, patients with clinical benefit had long-term disease control. The safety profile was acceptable. This drug class warrants further investigation, including identifying patients more likely to respond to this agent, or in combination with other agents.

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Section: Discussionsupporting

confidence: 86%

A phase 2 study of mocetinostat, a histone deacetylase inhibitor, in relapsed or refractory lymphoma

et al. 2017

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“…Romidepsin, a pan-HDAC inhibitor, is also approved for use in CTCL patients as well as for relapsed and refractory PTCL. A third inhibitor, the pan-HDAC inhibitor Belinostat, was also more recently approved for relapsed and refractory PTCL cases [160,161]. The overall responses were 25% for Romidepsin and 26% for Belinostat [162,163].…”

Section: Current Therapies and Novel Approachesmentioning

confidence: 99%

Emerging therapeutic targets in myeloproliferative neoplasms and peripheral T-cell leukemia and lymphomas

Orlova

Wingelhofer

Neubauer

et al. 2017

Expert Opinion on Therapeutic Targets

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Introduction: Hematopoietic neoplasms are often driven by gain-of-function mutations of the JAK-STAT pathway together with mutations in chromatin remodeling and DNA damage control pathways. The interconnection between the JAK-STAT pathway, epigenetic regulation or DNA damage control is still poorly understood in cancer cell biology. Areas covered: Here, we focus on a broader description of mutational insights into myeloproliferative neoplasms and peripheral T-cell leukemia and lymphomas, since sequencing efforts have identified similar combinations of driver mutations in these diseases covering different lineages. We summarize how these pathways might be interconnected in normal or cancer cells, which have lost differentiation capacity and drive oncogene transcription. Expert opinion: Due to similarities in driver mutations including epigenetic enzymes, JAK-STAT pathway activation and mutated checkpoint control through TP53, we hypothesize that similar therapeutic approaches could be of benefit in these diseases. We give an overview of how driver mutations in these malignancies contribute to hematopoietic cancer initiation or progression, and how these pathways can be targeted with currently available tools.

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“…Examples include vorinostat (3) 13) and romidepsin (4) 14) for cutaneous T-cell lymphoma; belinostat (5) 15) for peripheral T-cell lymphoma; and panobinostat (6) 16) for use in the combination therapy for recurrent multiple myeloma with bortezomib and dexamethasone (Fig. 2).…”

Section: )mentioning

confidence: 99%

False HDAC Inhibition by Aurone Compound

Itoh

Suzuki

Matsui

et al. 2016

CHEMICAL & PHARMACEUTICAL BULLETIN

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Fluorescence assays are useful tools for estimating enzymatic activity. Their simplicity and manageability make them suitable for screening enzyme inhibitors in drug discovery studies. However, researchers need to pay attention to compounds that show auto-fluorescence and quench fluorescence, because such compounds lower the accuracy of the fluorescence assay systems by producing false-positive or negative results. In this study, we found that aurone compound 7, which has been reported as a histone deacetylase (HDAC) inhibitor, gave false-positive results. Although compound 7 was identified by an in vitro HDAC fluorescence assay, it did not show HDAC inhibitory activity in a cell-based assay, leading us to suspect its in vitro HDAC inhibitory activity. As a result of verification experiments, we found that compound 7 interferes with the HDAC fluorescence assay by quenching the HDAC fluorescence signal. Our findings underscore the faults of fluorescence assays and call attention to careless interpretation.Key words fluorescence assay; histone deacetylase (HDAC); drug discovery screening; enzymatic activityThe evaluation of enzymatic activity is essential for understanding the biology of an enzyme or identifying its inhibitors. At present, in vitro or cell-based fluorescence assays are often used for the estimation of enzymatic activity, or for high-throughput screening for drug candidates.1-4) For example, substrates bearing a fluorophore are available for estimating the activity of trypsin or caspase-3 or searching their inhibitors 5-7) (Figs. 1A-C). Trypsin or caspase-3 recognizes a particular amino acid or amino acid sequence in the fluorescent substrates and specifically cleaves the peptide bond of the C-terminus to release a fluorophore, such as 7-amino-4-methylcoumarin (AMC, 1) (Fig. 1A). Because N-acylated AMC (2) does not emit strong fluorescence, the detected fluorescence should correspond to the enzymatic activity (Figs. 1A-C); in this way, the enzymatic activity or inhibitory activity can be evaluated. Such assay systems based on fluorometric methods are frequently utilized in drug discovery studies.Assay systems based on fluorescent substrates are often used for evaluating the activity of histone deacetylases (HDACs).8-10) HDACs, which catalyze the deacetylation of acetyl lysine residues in histone or non-histone proteins, are an interesting molecular target of cancer therapeutic agents. 11)Many HDAC inhibitors have been identified 11,12) and some have been approved by the Food and Drug Administration (FDA). Examples include vorinostat (3) 13) and romidepsin (4) 14) for cutaneous T-cell lymphoma; belinostat (5) 15) for peripheral T-cell lymphoma; and panobinostat (6) 16) for use in the combination therapy for recurrent multiple myeloma with bortezomib and dexamethasone (Fig. 2). However, problems persist regarding the approved HDAC inhibitors, including adverse effects and limited additional indications. Therefore, explorative studies of novel HDAC inhibitors should be performed. To this end, fluoresc...

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Belinostat in patients with refractory or relapsed peripheral T-cell lymphoma: a perspective review

Cited by 91 publications

References 27 publications

A phase 2 study of mocetinostat, a histone deacetylase inhibitor, in relapsed or refractory lymphoma

A phase 2 study of mocetinostat, a histone deacetylase inhibitor, in relapsed or refractory lymphoma

Emerging therapeutic targets in myeloproliferative neoplasms and peripheral T-cell leukemia and lymphomas

False HDAC Inhibition by Aurone Compound

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