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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 -
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 -
Neuro-oncology Jul 2022Embryonal tumors of the CNS are the most common malignant tumors occurring in the first years of life. This study evaluated the feasibility and safety of incorporating... (Clinical Trial)
Clinical Trial
BACKGROUND
Embryonal tumors of the CNS are the most common malignant tumors occurring in the first years of life. This study evaluated the feasibility and safety of incorporating novel non-cytotoxic therapy with vorinostat and isotretinoin to an intensive cytotoxic chemotherapy backbone.
METHODS
PBTC-026 was a prospective multi-institutional clinical trial for children <48 months of age with newly diagnosed embryonal tumors of the CNS. Treatment included three 21-day cycles of induction therapy with vorinostat and isotretinoin, cisplatin, vincristine, cyclophosphamide, and etoposide; three 28-day cycles of consolidation therapy with carboplatin and thiotepa followed by stem cell rescue; and twelve 28-day cycles of maintenance therapy with vorinostat and isotretinoin. Patients with M0 medulloblastoma (MB) received focal radiation following consolidation therapy. Molecular classification was by DNA methylation array.
RESULTS
Thirty-one patients with median age of 26 months (range 6-46) received treatment on study; 19 (61%) were male. Diagnosis was MB in 20 and supratentorial CNS embryonal tumor in 11. 24/31 patients completed induction therapy within a pre-specified feasibility window of 98 days. Five-year progression-free survival (PFS) and overall survival (OS) for all 31 patients were 55 ± 15 and 61 ± 13, respectively. Five-year PFS was 42 ± 13 for group 3 MB (n = 12); 80 ± 25 for SHH MB (n = 5); 33 ± 19 for embryonal tumor with multilayered rosettes (ETMR, n = 6).
CONCLUSION
It was safe and feasible to incorporate vorinostat and isotretinoin into an intensive chemotherapy regimen. Further study to define efficacy in this high-risk group of patients is warranted.
Topics: Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Cerebellar Neoplasms; Child; Child, Preschool; Cyclophosphamide; Etoposide; Female; Humans; Infant; Isotretinoin; Male; Medulloblastoma; Neoplasms, Germ Cell and Embryonal; Neuroectodermal Tumors, Primitive; Prospective Studies; Vincristine; Vorinostat
PubMed: 34935967
DOI: 10.1093/neuonc/noab293 -
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 -
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 -
Neuro-oncology Jul 2022
Topics: Brain Neoplasms; Child; Child, Preschool; Feasibility Studies; Humans; Infant; Isotretinoin; Vorinostat
PubMed: 35287175
DOI: 10.1093/neuonc/noac065 -
Journal of Clinical Oncology : Official... Nov 2021I-metaiodobenzylguanidine (MIBG) is an active radiotherapeutic for neuroblastoma. The primary aim of this trial was to identify which of three MIBG regimens was likely... (Randomized Controlled Trial)
Randomized Controlled Trial
Randomized Phase II Trial of MIBG Versus MIBG, Vincristine, and Irinotecan Versus MIBG and Vorinostat for Patients With Relapsed or Refractory Neuroblastoma: A Report From NANT Consortium.
PURPOSE
I-metaiodobenzylguanidine (MIBG) is an active radiotherapeutic for neuroblastoma. The primary aim of this trial was to identify which of three MIBG regimens was likely associated with the highest true response rate.
PATIENTS AND METHODS
Patients 1-30 years were eligible if they had relapsed or refractory neuroblastoma, at least one MIBG-avid site, and adequate autologous stem cells. Patients received MIBG 18 mCi/kg on day 1 and autologous stem cell on day 15. Patients randomly assigned to arm A received only MIBG; patients randomly assigned to arm B received intravenous vincristine on day 0 and irinotecan daily on days 0-4; patients randomly assigned to arm C received vorinostat (180 mg/m/dose) orally once daily on days 1 to 12. The primary end point was response after one course by New Approaches to Neuroblastoma Therapy criteria. The trial was designed with 105 patients to ensure an 80% chance that the arm with highest response rate was selected.
RESULTS
One hundred fourteen patients were enrolled, with three ineligible and six unevaluable, leaving 105 eligible and evaluable patients (36 in arm A, 35 in arm B, and 34 in arm C; 55 boys; and median age 6.5 years). After one course, the response rates (partial response or better) on arms A, B, and C were 14% (95% CI, 5 to 30), 14% (5 to 31), and 32% (18 to 51). An additional five, five, and four patients met New Approaches to Neuroblastoma Therapy Minor Response criteria on arms A, B, and C, respectively. On arms A, B, and C, rates of any grade 3+ nonhematologic toxicity after first course were 19%, 49%, and 35%.
CONCLUSION
Vorinostat and MIBG is likely the arm with the highest true response rate, with manageable toxicity. Vincristine and irinotecan do not appear to improve the response rate to MIBG and are associated with increased toxicity.
Topics: 3-Iodobenzylguanidine; Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Drug Resistance, Neoplasm; Female; Follow-Up Studies; Humans; Infant; Irinotecan; Male; Neoplasm Recurrence, Local; Neuroblastoma; Prognosis; Prospective Studies; Salvage Therapy; Survival Rate; Vincristine; Vorinostat; Young Adult
PubMed: 34270348
DOI: 10.1200/JCO.21.00703 -
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 -
Journal of Cellular Physiology Jan 2021Glioblastoma (GBM) is an aggressive brain tumor and drug resistance remains a major barrier for therapeutics. Epigenetic alterations are implicated in GBM pathogenesis,...
Glioblastoma (GBM) is an aggressive brain tumor and drug resistance remains a major barrier for therapeutics. Epigenetic alterations are implicated in GBM pathogenesis, and epigenetic modulators including histone deacetylase (HDAC) inhibitors are exploited as promising anticancer therapies. Here, we demonstrate that phospholipase D1 (PLD1) is a transcriptional target of HDAC inhibitors and confers resistance to HDAC inhibitor in GBM. Treatment of vorinostat upregulates PLD1 through PKCζ-Sp1 axis. Vorinostat induces dynamic changes in the chromatin structure and transcriptional machinery associated with PLD1 promoter region. Cotreatment of vorinostat with PLD1 inhibitor further attenuates invasion, angiogenesis, colony-forming capacity, and self-renewal capacity, compared with those of either treatment. PLD1 inhibitor overcomes resistance to vorinostat in GBM cells intracranial GBM tumors. Our finding provides new insight into the role of PLD1 as a target of resistance to vorinostat, and PLD1 inhibitor might provide the basis for therapeutic combinations with improved efficacy of HDAC inhibitor.
Topics: Animals; Antineoplastic Agents; Brain Neoplasms; Cell Line, Tumor; Chromatin; Drug Resistance, Neoplasm; Epigenomics; Glioblastoma; Histone Deacetylase Inhibitors; Humans; Mice; Mice, Inbred C57BL; Mice, Nude; Neovascularization, Pathologic; Phospholipase D; Promoter Regions, Genetic; Transcription, Genetic; U937 Cells; Up-Regulation; Vorinostat
PubMed: 32869317
DOI: 10.1002/jcp.29882