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The Lancet. Oncology Sep 2018Cutaneous T-cell lymphomas are rare non-Hodgkin lymphomas with substantial morbidity and mortality in advanced disease stages. We compared the efficacy of mogamulizumab,... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Cutaneous T-cell lymphomas are rare non-Hodgkin lymphomas with substantial morbidity and mortality in advanced disease stages. We compared the efficacy of mogamulizumab, a novel monoclonal antibody directed against C-C chemokine receptor 4, with vorinostat in patients with previously treated cutaneous T-cell lymphoma.
METHODS
In this open-label, international, phase 3, randomised controlled trial, we recruited patients with relapsed or refractory mycosis fungoides or Sézary syndrome at 61 medical centres in the USA, Denmark, France, Italy, Germany, the Netherlands, Spain, Switzerland, the UK, Japan, and Australia. Eligible patients were aged at least 18 years (in Japan, ≥20 years), had failed (for progression or toxicity as assessed by the principal investigator) at least one previous systemic therapy, and had an Eastern Cooperative Oncology Group performance score of 1 or less and adequate haematological, hepatic, and renal function. Patients were randomly assigned (1:1) using an interactive voice web response system to mogamulizumab (1·0 mg/kg intravenously on a weekly basis for the first 28-day cycle, then on days 1 and 15 of subsequent cycles) or vorinostat (400 mg daily). Stratification was by cutaneous T-cell lymphoma subtype (mycosis fungoides vs Sézary syndrome) and disease stage (IB-II vs III-IV). Since this study was open label, patients and investigators were not masked to treatment assignment. The primary endpoint was progression-free survival by investigator assessment in the intention-to-treat population. Patients who received one or more doses of study drug were included in the safety analyses. This study is ongoing, and enrolment is complete. This trial was registered with ClinicalTrials.gov, number NCT01728805.
FINDINGS
Between Dec 12, 2012, and Jan 29, 2016, 372 eligible patients were randomly assigned to receive mogamulizumab (n=186) or vorinostat (n=186), comprising the intention-to-treat population. Two patients randomly assigned to mogamulizumab withdrew consent before receiving study treatment; thus, 370 patients were included in the safety population. Mogamulizumab therapy resulted in superior investigator-assessed progression-free survival compared with vorinostat therapy (median 7·7 months [95% CI 5·7-10·3] in the mogamulizumab group vs 3·1 months [2·9-4·1] in the vorinostat group; hazard ratio 0·53, 95% CI 0·41-0·69; stratified log-rank p<0·0001). Grade 3-4 adverse events of any cause were reported in 75 (41%) of 184 patients in the mogamulizumab group and 76 (41%) of 186 patients in the vorinostat group. The most common serious adverse events of any cause were pyrexia in eight (4%) patients and cellulitis in five (3%) patients in the mogamulizumab group; and cellulitis in six (3%) patients, pulmonary embolism in six (3%) patients, and sepsis in five (3%) patients in the vorinostat group. Two (67%) of three on-treatment deaths with mogamulizumab (due to sepsis and polymyositis) and three (33%) of nine on-treatment deaths with vorinostat (two due to pulmonary embolism and one due to bronchopneumonia) were considered treatment-related.
INTERPRETATION
Mogamulizumab significantly prolonged progression-free survival compared with vorinostat, and could provide a new, effective treatment for patients with mycosis fungoides and, importantly, for Sézary syndrome, a subtype that represents a major therapeutic challenge in cutaneous T-cell lymphoma.
FUNDING
Kyowa Kirin.
Topics: Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Australia; Drug Administration Schedule; Drug Resistance, Neoplasm; Europe; Female; Histone Deacetylase Inhibitors; Humans; Japan; Lymphoma, T-Cell, Cutaneous; Male; Middle Aged; Mycosis Fungoides; Neoplasm Recurrence, Local; Neoplasm Staging; Progression-Free Survival; Sezary Syndrome; Time Factors; United States; Vorinostat
PubMed: 30100375
DOI: 10.1016/S1470-2045(18)30379-6 -
Advanced Science (Weinheim,... Nov 2023One major characteristic of tumor cells is the aberrant activation of epigenetic regulatory elements, which remodel the tumor transcriptome and ultimately...
One major characteristic of tumor cells is the aberrant activation of epigenetic regulatory elements, which remodel the tumor transcriptome and ultimately promote cancer progression and drug resistance. However, the oncogenic functions and mechanisms of ovarian cancer (OC) remain elusive. Here, super-enhancer (SE) regulatory elements that are aberrantly activated in OC are identified and it is found that SEs drive the relative specific expression of the transcription factor KLF5 in OC patients and poly(ADP-ribose) polymerase inhibitor (PARPi)-resistant patients. KLF5 expression is associated with poor outcomes in OC patients and can drive tumor progression in vitro and in vivo. Mechanistically, KLF5 forms a transcriptional complex with EHF and ELF3 and binds to the promoter region of RAD51 to enhance its transcription, strengthening the homologous recombination repair (HRR) pathway. Notably, the combination of suberoylanilide hydroxamic acid (SAHA) and olaparib significantly inhibits tumor growth and metastasis of PARPi-resistant OC cells with high KLF5. In conclusion, it is discovered that SEs-driven KLF5 is a key regulatory factor in OC progression and PARPi resistance; and potential therapeutic strategies for OC patients with PARPi resistance and high KLF5 are identified.
Topics: Humans; Female; Poly(ADP-ribose) Polymerase Inhibitors; Drug Resistance, Neoplasm; Antineoplastic Agents; Ovarian Neoplasms; Vorinostat; Kruppel-Like Transcription Factors
PubMed: 37702443
DOI: 10.1002/advs.202304638 -
Gastroenterology Apr 2024The incidence of Crohn's disease (CD) continues to increase worldwide. The contribution of CD4 cell populations remains to be elucidated. We aimed to provide an in-depth...
BACKGROUND & AIMS
The incidence of Crohn's disease (CD) continues to increase worldwide. The contribution of CD4 cell populations remains to be elucidated. We aimed to provide an in-depth transcriptional assessment of CD4 T cells driving chronic inflammation in CD.
METHODS
We performed single-cell RNA-sequencing in CD4 T cells isolated from ileal biopsies of patients with CD compared with healthy individuals. Cells underwent clustering analysis, followed by analysis of gene signaling networks. We overlapped our differentially expressed genes with publicly available microarray data sets and performed functional in vitro studies, including an in vitro suppression assay and organoid systems, to model gene expression changes observed in CD regulatory T (Treg) cells and to test predicted therapeutics.
RESULTS
We identified 5 distinct FOXP3 regulatory Treg subpopulations. Tregs isolated from healthy controls represent the origin of pseudotemporal development into inflammation-associated subtypes. These proinflammatory Tregs displayed a unique responsiveness to tumor necrosis factor-α signaling with impaired suppressive activity in vitro and an elevated cytokine response in an organoid coculture system. As predicted in silico, the histone deacetylase inhibitor vorinostat normalized gene expression patterns, rescuing the suppressive function of FOXP3 cells in vitro.
CONCLUSIONS
We identified a novel, proinflammatory FOXP3 T cell subpopulation in patients with CD and developed a pipeline to specifically target these cells using the US Food and Drug Administration-approved drug vorinostat.
Topics: Humans; Crohn Disease; Vorinostat; T-Lymphocytes, Regulatory; Inflammation; Forkhead Transcription Factors
PubMed: 38211712
DOI: 10.1053/j.gastro.2024.01.007 -
Pharmacogenomics Nov 2016The histone deacetylase inhibitor valproic acid (VPA) has been used for many decades in neurology and psychiatry. The more recent introduction of the histone deacetylase... (Review)
Review
The histone deacetylase inhibitor valproic acid (VPA) has been used for many decades in neurology and psychiatry. The more recent introduction of the histone deacetylase inhibitors (HDIs) belinostat, romidepsin and vorinostat for treatment of hematological malignancies indicates the increasing popularity of these agents. Belinostat, romidepsin and vorinostat are metabolized or transported by polymorphic enzymes or drug transporters. Thus, genotype-directed dosing could improve pharmacotherapy by reducing the risk of toxicities or preventing suboptimal treatment. This review provides an overview of clinical studies on the effects of polymorphisms on the pharmacokinetics, efficacy or toxicities of HDIs including belinostat, romidepsin, vorinostat, panobinostat, VPA and a number of novel compounds currently being tested in Phase I and II trials. Although pharmacogenomic studies for HDIs are scarce, available data indicate that therapy with belinostat (UGT1A1), romidepsin (ABCB1), vorinostat (UGT2B17) or VPA (UGT1A6) could be optimized by upfront genotyping.
Topics: Depsipeptides; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Indoles; Panobinostat; Pharmacogenetics; Sulfonamides; Valproic Acid; Vorinostat
PubMed: 27767376
DOI: 10.2217/pgs-2016-0113 -
Biotechnology Journal Mar 2023Recombinant adeno-associated virus (rAAV) has established itself as a highly efficacious gene delivery vector with a well characterised safety profile allowing broad...
Recombinant adeno-associated virus (rAAV) has established itself as a highly efficacious gene delivery vector with a well characterised safety profile allowing broad clinical application. Recent successes in rAAV-mediated gene therapy clinical trials will continue to drive demand for improved rAAV production processes to reduce costs. Here, we demonstrate that small molecule bioactive chemical additives can significantly increase recombinant AAV vector production by human embryonic kidney (HEK) cells up to three-fold. Nocodazole (an anti-mitotic agent) and M344 (a selective histone deacetylase inhibitor) were identified as positive regulators of rAAV8 genome titre in a microplate screening assay. Addition of nocodazole to triple-transfected HEK293 suspension cells producing rAAV arrested cells in G2/M phase, increased average cell volume and reduced viable cell density relative to untreated rAAV producing cells at harvest. Final crude genome vector titre from nocodazole treated cultures was >2-fold higher compared to non-treated cultures. Further investigation showed nocodazole addition to cultures to be time critical. Genome titre improvement was found to be scalable and serotype independent across two distinct rAAV serotypes, rAAV8 and rAAV9. Furthermore, a combination of M344 and nocodazole produced a positive additive effect on rAAV8 genome titre, resulting in a three-fold increase in genome titre compared to untreated cells.
Topics: Humans; Genetic Vectors; HEK293 Cells; Dependovirus; Nocodazole; Vorinostat
PubMed: 36495042
DOI: 10.1002/biot.202200450 -
European Review For Medical and... Jul 2020Vorinostat is a drug used to treat cutaneous T cell lymphoma whose action mechanism is based on Histone Deacetylase inhibition. Histone Deacetylases are a family of... (Review)
Review
OBJECTIVE
Vorinostat is a drug used to treat cutaneous T cell lymphoma whose action mechanism is based on Histone Deacetylase inhibition. Histone Deacetylases are a family of enzymes that remove acetyl groups from histone and non-histone proteins that control many crucial processes, such as gene regulation, cell cycle progression, differentiation, and apoptosis. Histone Deacetylase homologues are also expressed in parasites of the genus Plasmodium, Leishmania, Cryptosporidium, Schistosoma, Entamoeba, and others. In this way, antiparasitic properties of Vorinostat have been explored. The aim of this review is to report the current state knowledge of Vorinostat as antiparasitic drug against Plasmodium, Leishmania, Cryptosporidium, Schistosoma and Entamoeba in order to support future investigation in this field.
MATERIALS AND METHODS
The authors revised the recent and relevant literature concerning the topic and discussed advances and limitations of studies on Vorinostat as potential drug to treat human parasitic diseases.
RESULTS
Vorinostat has been efficient in vitro and, in some cases, in vivo, against parasites that cause parasitic diseases, such as malaria, leishmaniasis, cryptosporidiosis, amoebiasis, and schistosomiasis.
CONCLUSIONS
In vitro and in vivo models have demonstrated the antiparasitic activity of Vorinostat, however, the challenge is to assay its activity in animal models and to evaluate if Vorinostat is safe for humans as new alternative to treat human parasitic infections.
Topics: Animals; Antiparasitic Agents; Drug Repositioning; Histone Deacetylase Inhibitors; Histone Deacetylases; Host-Parasite Interactions; Humans; Parasites; Parasitic Diseases; Protozoan Proteins; Vorinostat
PubMed: 32706080
DOI: 10.26355/eurrev_202007_21909 -
Methods in Molecular Biology (Clifton,... 2016Lysine acetylation in proteins is one of the most abundant posttranslational modifications in eukaryotic cells. The dynamic homeostasis of lysine acetylation and...
Lysine acetylation in proteins is one of the most abundant posttranslational modifications in eukaryotic cells. The dynamic homeostasis of lysine acetylation and deacetylation is dictated by the action of histone acetyltransferases (HAT) and histone deacetylases (HDAC). Important substrates for HATs and HDACs are histones, where lysine acetylation generally leads to an open and transcriptionally active chromatin conformation. Histone deacetylation forces the compaction of the chromatin with subsequent inhibition of transcription and reduced gene expression. Unbalanced HAT and HDAC activity, and therefore aberrant histone acetylation, has been shown to be involved in tumorigenesis and progression of malignancy in different types of cancer. Therefore, the development of HDAC inhibitors (HDIs) as therapeutic agents against cancer is of great interest. However, treatment with HDIs can also affect the acetylation status of many other non-histone proteins which play a role in different pathways including angiogenesis, cell cycle progression, autophagy and apoptosis. These effects have led HDIs to become anticancer agents, which can initiate apoptosis in tumor cells. Hematological malignancies in particular are responsive to HDIs, and four HDIs have already been approved as anticancer agents. There is a strong interest in finding adequate biomarkers to predict the response to HDI treatment. This chapter provides information on how to assess HDAC activity in vitro and determine the potency of HDIs on different HDACs. It also gives information on how to analyze cellular markers following HDI treatment and to analyze tissue biopsies from HDI-treated patients. Finally, a protocol is provided on how to detect HDI sensitivity determinants in human cells, based on a pRetroSuper shRNA screen upon HDI treatment.
Topics: Acetylation; Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Drug Screening Assays, Antitumor; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; HeLa Cells; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Hydroxamic Acids; Neoplasms; Vorinostat
PubMed: 27246222
DOI: 10.1007/978-1-4939-3667-0_19 -
Clinical Cancer Research : An Official... Sep 2023Histone deacetylase (HDAC) inhibition has been shown to induce pharmacologic "BRCAness" in cancer cells with proficient DNA repair activity. This provides a rationale...
PURPOSE
Histone deacetylase (HDAC) inhibition has been shown to induce pharmacologic "BRCAness" in cancer cells with proficient DNA repair activity. This provides a rationale for exploring combination treatments with HDAC and PARP inhibition in cancer types that are insensitive to single-agent PARP inhibitors (PARPi). Here, we report the concept and characterization of a novel bifunctional PARPi (kt-3283) with dual activity toward PARP1/2 and HDAC enzymes in Ewing sarcoma cells.
EXPERIMENTAL DESIGN
Inhibition of PARP1/2 and HDAC was measured using PARP1/2, HDAC activity, and PAR formation assays. Cytotoxicity was assessed by IncuCyte live cell imaging, CellTiter-Glo, and spheroid assays. Cell-cycle profiles were determined using propidium iodide staining and flow cytometry. DNA damage was examined by γH2AX expression and comet assay. Inhibition of metastatic potential by kt-3283 was evaluated via ex vivo pulmonary metastasis assay (PuMA).
RESULTS
Compared with FDA-approved PARP (olaparib) and HDAC (vorinostat) inhibitors, kt-3283 displayed enhanced cytotoxicity in Ewing sarcoma models. The kt-3283-induced cytotoxicity was associated with strong S and G2-M cell-cycle arrest in nanomolar concentration range and elevated DNA damage as assessed by γH2AX tracking and comet assays. In three-dimensional spheroid models of Ewing sarcoma, kt-3283 showed efficacy in lower concentrations than olaparib and vorinostat, and kt-3283 inhibited colonization of Ewing sarcoma cells in the ex vivo PuMA model.
CONCLUSIONS
Our data demonstrate the preclinical justification for studying the benefit of dual PARP and HDAC inhibition in the treatment of Ewing sarcoma in a clinical trial and provides proof-of-concept for a bifunctional single-molecule therapeutic strategy.
Topics: Animals; Humans; Poly(ADP-ribose) Polymerase Inhibitors; Sarcoma, Ewing; Histone Deacetylase Inhibitors; Vorinostat; Puma
PubMed: 37279093
DOI: 10.1158/1078-0432.CCR-22-3897 -
Neuro-oncology Jul 2022
Topics: Brain Neoplasms; Child; Child, Preschool; Feasibility Studies; Humans; Infant; Isotretinoin; Vorinostat
PubMed: 35287175
DOI: 10.1093/neuonc/noac065 -
The Turkish Journal of Gastroenterology... May 2023Inflammatory bowel diseases are multifactorial, chronic, continuous, relapsing, and immune-mediated diseases of the gastrointestinal tract. It has been believed that...
Inflammatory bowel diseases are multifactorial, chronic, continuous, relapsing, and immune-mediated diseases of the gastrointestinal tract. It has been believed that mechanisms underlying inflammatory bowel diseases include genetic predisposition, environmental factors, and altered immune response to the gut microbiome. The epigenetic modulation takes place via chromatin modifications, including phosphorylation, acetylation, methylation, sumoylation, and ubiquitination. The methylation levels of colonic tissue were found well correlated to blood samples in inflammatory bowel diseases. Moreover, the methylation level of specific genes was different between Crohn's disease and ulcerative colitis. It has been shown that the enzymes affecting histone modifications like histone deacetylases and histone acetyltransferases do not act solely on histones but also affect the acetylation of many proteins such as p53 and STAT3. It has been already shown that a nonselective histone deacetylase inhibitor, Vorinostat (SAHA), which is currently being used in several cancer treatments, showed anti-inflammatory activities in mouse models. Among epigenetic alterations, long non-coding RNAs and microRNAs play significant roles in T-cell maturation, differentiation, activation, and senility. The long non-coding RNA and microRNA expression profiles can perfectly separate inflammatory bowel disease patients from healthy controls and are remarked as biomarkers of inflammatory bowel diseases. Overall, many studies have shown that epigenetic inhibitors can target significant signal pathways in the pathogenesis of inflammatory bowel diseases, and the impact of epigenetic inhibitors is being studied in clinical trials. In conclusion, exploring more epigenetic pathways regarding inflammatory bowel disease pathogenesis will help us to discover therapeutic targets and new drugs and agents targeting miRNAs in inflammatory bowel diseases. In general, discovering epigenetic targets could improve the diagnosis and treatment of inflammatory bowel diseases.
Topics: Animals; Mice; Epigenesis, Genetic; Inflammatory Bowel Diseases; Histones; MicroRNAs; Vorinostat; DNA Methylation
PubMed: 37158530
DOI: 10.5152/tjg.2023.22515