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Journal of the European Academy of... Feb 2023Cutaneous T-cell lymphomas (CTCL) are rare types of non-Hodgkin lymphoma, which present in skin. Mycosis fungoides (MF) and Sézary syndrome (SS) are subtypes which make... (Clinical Trial)
Clinical Trial
BACKGROUND
Cutaneous T-cell lymphomas (CTCL) are rare types of non-Hodgkin lymphoma, which present in skin. Mycosis fungoides (MF) and Sézary syndrome (SS) are subtypes which make up two-thirds of all CTCL cases. The phase 3 MAVORIC study (NCT01728805) compared mogamulizumab to vorinostat in MF and SS patients, with post hoc data showing a trend for higher efficacy in mogamulizumab-treated patients as baseline blood tumour burden increases.
OBJECTIVES
The aim of this study was to use updated post hoc analyses in order to examine the efficacy of mogamulizumab and vorinostat in MF patients when stratified by baseline blood involvement and to determine what factors affect time-to-global and time-to-skin response to inform clinical follow-up.
METHODS
Post hoc analyses were carried out using data from MAVORIC. Overall response rate (ORR), progression-free survival (PFS) and time-to-next-treatment (TTNT) data were used to assess efficacy in patients with MF. Time-to-global response (TTR) was examined by disease subtype, by blood involvement in MF patients, and time-to-skin response was examined by blood involvement in MF patients.
RESULTS
Numerically superior results were seen for ORR, PFS and TTNT in mogamulizumab-treated patients with MF compared with vorinostat, with a trend for outcomes improving with increasing baseline blood class. Statistically significant results for mogamulizumab compared with vorinostat were seen for MF B1 pts for PFS (8.43 vs. 2.83 months, p = 0.003) and TTNT (11.9 vs. 3.13 months, p = 0.002), and for MF B2 pts for ORR (46.2 vs. 9.1 months, p = 0.033).
CONCLUSIONS
In mogamulizumab-treated MF patients, ORR and PFS were seen to improve with increasing blood involvement, which led to improved TTNT. TTR was more predictable for mogamulizumab-treated MF patients with blood involvement, and skin response may take longer than previously reported in some patients.
Topics: Humans; Lymphoma, T-Cell, Cutaneous; Mycosis Fungoides; Sezary Syndrome; Skin Neoplasms; Vorinostat
PubMed: 35993803
DOI: 10.1111/jdv.18549 -
Journal of the European Academy of... Oct 2023
Topics: Humans; Pemphigoid, Bullous; Vorinostat; Immunoglobulin G
PubMed: 37191129
DOI: 10.1111/jdv.19209 -
International Journal of Medical... 2019T-cell lymphomas are a heterogeneous group of cancers with different pathogenesis and poor prognosis. Histone deacetylases (HDACs) are epigenetic modifiers that modulate... (Review)
Review
T-cell lymphomas are a heterogeneous group of cancers with different pathogenesis and poor prognosis. Histone deacetylases (HDACs) are epigenetic modifiers that modulate many key biological processes. In recent years, HDACs have been fully investigated for their roles and potential as drug targets in T-cell lymphomas. In this review, we have deciphered the modes of action of HDACs, HDAC inhibitors as single agents, and HDACs guided combination therapies in T-cell lymphomas. The overview of HDACs on the stage of T-cell lymphomas, and HDACs guided therapies both as single agents and combination regimens endow great opportunities for the cure of T-cell lymphomas.
Topics: Antineoplastic Combined Chemotherapy Protocols; Autophagy; Cytokines; Depsipeptides; Epigenesis, Genetic; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Hydroxamic Acids; Lymphoma, T-Cell; Molecular Targeted Therapy; Sulfonamides; Vorinostat
PubMed: 30911277
DOI: 10.7150/ijms.30154 -
Blood Advances Aug 2018Sézary syndrome (SS) is an aggressive leukemic variant of cutaneous T-cell lymphoma (CTCL) with a median life expectancy of less than 4 years. Although initial...
Sézary syndrome (SS) is an aggressive leukemic variant of cutaneous T-cell lymphoma (CTCL) with a median life expectancy of less than 4 years. Although initial treatment responses are often good, the vast majority of patients with SS fail to respond to ongoing therapy. We hypothesize that malignant T cells are highly heterogeneous and harbor subpopulations of SS cells that are both sensitive and resistant to treatment. Here, we investigate the presence of single-cell heterogeneity and resistance to histone deacetylase inhibitors (HDACi) within primary malignant T cells from patients with SS. Using single-cell RNA sequencing and flow cytometry, we find that malignant T cells from all investigated patients with SS display a high degree of single-cell heterogeneity at both the mRNA and protein levels. We show that this heterogeneity divides the malignant cells into distinct subpopulations that can be isolated by their expression of different surface antigens. Finally, we show that treatment with HDACi (suberanilohydroxamic acid and romidepsin) selectively eliminates some subpopulations while leaving other subpopulations largely unaffected. In conclusion, we show that patients with SS display a high degree of single-cell heterogeneity within the malignant T-cell population, and that distinct subpopulations of malignant T cells carry HDACi resistance. Our data point to the importance of understanding the heterogeneous nature of malignant SS cells in each individual patient to design combinational and new therapies to counter drug resistance and treatment failure.
Topics: Aged; Aged, 80 and over; Depsipeptides; Drug Resistance, Neoplasm; Female; Flow Cytometry; Histone Deacetylase Inhibitors; Humans; Male; Middle Aged; Sezary Syndrome; T-Lymphocytes; Vorinostat
PubMed: 30139925
DOI: 10.1182/bloodadvances.2018022608 -
Haematologica Feb 2024Outcomes after programmed death-1 (PD-1) blockade in B-cell lymphomas are disappointing with few durable responses. Histone deacetylase inhibitors exhibit favorable...
Outcomes after programmed death-1 (PD-1) blockade in B-cell lymphomas are disappointing with few durable responses. Histone deacetylase inhibitors exhibit favorable immunomodulatory effects and demonstrate synergistic anti-tumor immune responses with anti-PD-1 therapy in preclinical models. We, therefore, developed a phase I study to evaluate the safety and preliminary efficacy of pembrolizumab with vorinostat in relapsed/refractory B-cell lymphomas. Patients were treated in a dose-escalation cohort using a Rolling 6 design followed by an expansion cohort at the recommended phase II dose (R2PD). Fifty-two patients were enrolled (32 Hodgkin and 20 non-Hodgkin lymphoma [NHL]). Here, we report safety data from the dose escalation cohort, and the toxicity and efficacy within NHL patients. Vorinostat was administered twice daily on days 1-5 and 8-12 (dose-level [DL]1: 100 mg; DL2: 200 mg) and pembrolizumab (200 mg) was administered on day 1 of each 3-week cycle. Of six patients treated at DL1, one had a dose-limiting toxicity (DLT) (Stevens-Johnson syndrome [SJS]), and one of six had a DLT at DL2 (thromboembolism); therefore, DL2 was the RP2D. The patient developing SJS was treated with corticosteroids, infliximab, and cyclosporine but ultimately died of invasive fungal infection from the extensive immunosuppression used to treat the SJS. The most common adverse events were hypertension, diarrhea, and cytopenias. Of 20 NHL patients, nine had follicular lymphoma (FL) and 11 had diffuse large B-cell lymphoma (DLBCL). Five DLBCL patients had primary mediastinal B-cell lymphoma (PMBL). The complete and overall response rates (CR and ORR) were 11% and 22% for FL and 45% and 55% for all DLBCL. Amongst DLBCL, the CR and ORR was 80% and 80% for PMBL and 17% and 33% for non-PMBL. In conclusion, pembrolizumab with vorinostat was tolerable and produced responses in relapsed/refractory B-cell NHL, with particularly notable efficacy in PMBL (clinicaltrials gov. Identifier: NCT03150329).
Topics: Humans; Vorinostat; Neoplasm Recurrence, Local; Lymphoma, Non-Hodgkin; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Follicular; Antibodies, Monoclonal, Humanized
PubMed: 37470137
DOI: 10.3324/haematol.2023.283002 -
Journal of Medicinal Chemistry Jun 2023Histone deacetylases (HDACs) are enzymes pursued as drug targets in various cancers and several non-oncological conditions, such as inflammation and neurodegenerative... (Review)
Review
Histone deacetylases (HDACs) are enzymes pursued as drug targets in various cancers and several non-oncological conditions, such as inflammation and neurodegenerative disorders. In the past decade, HDAC inhibitors (HDACi) have emerged as relevant pharmaceuticals, with many efforts devoted to the development of new representatives. However, the growing safety concerns regarding the established hydroxamic acid-based HDAC inhibitors tend to drive current research more toward the design of inhibitors bearing alternative zinc-binding groups (ZBGs). This Perspective presents an overview of all non-hydroxamic acid ZBGs that have been incorporated into the clinically approved prototypical HDACi, suberoylanilide hydroxamic acid (vorinostat). This provides the unique opportunity to compare the inhibition potential and biological effects of different ZBGs in a direct way, as the compounds selected for this Perspective differ only in their ZBG. To that end, different strategies used to select a ZBG, its properties, activity, and liabilities are discussed.
Topics: Vorinostat; Histone Deacetylase Inhibitors; Hydroxamic Acids; Histone Deacetylases; Zinc
PubMed: 37276138
DOI: 10.1021/acs.jmedchem.3c00226 -
International Journal of Cancer Apr 2023The mitochondrion is a gatekeeper of apoptotic processes, and mediates drug resistance to several chemotherapy agents used to treat cancer. Neuroblastoma is a common...
The mitochondrion is a gatekeeper of apoptotic processes, and mediates drug resistance to several chemotherapy agents used to treat cancer. Neuroblastoma is a common solid cancer in young children with poor clinical outcomes following conventional chemotherapy. We sought druggable mitochondrial protein targets in neuroblastoma cells. Among mitochondria-associated gene targets, we found that high expression of the mitochondrial adenine nucleotide translocase 2 (SLC25A5/ANT2), was a strong predictor of poor neuroblastoma patient prognosis and contributed to a more malignant phenotype in pre-clinical models. Inhibiting this transporter with PENAO reduced cell viability in a panel of neuroblastoma cell lines in a TP53-status-dependant manner. We identified the histone deacetylase inhibitor, suberanilohydroxamic acid (SAHA), as the most effective drug in clinical use against mutant TP53 neuroblastoma cells. SAHA and PENAO synergistically reduced cell viability, and induced apoptosis, in neuroblastoma cells independent of TP53-status. The SAHA and PENAO drug combination significantly delayed tumour progression in pre-clinical neuroblastoma mouse models, suggesting that these clinically advanced inhibitors may be effective in treating the disease.
Topics: Animals; Mice; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Histone Deacetylase Inhibitors; Histones; Hydroxamic Acids; Mitochondria; Neuroblastoma; Vorinostat; Adenine Nucleotide Translocator 2
PubMed: 36346110
DOI: 10.1002/ijc.34349 -
Journal of Separation Science Feb 2023While histone deacetylase inhibitors, such as vorinostat, demonstrate a significant effect against hematological cancers, their application for solid tumor treatment is...
Box-Behnken assisted development and validation of high-performance liquid chromatography method for the simultaneous determination of doxorubicin and vorinostat in polymeric nanoparticles.
While histone deacetylase inhibitors, such as vorinostat, demonstrate a significant effect against hematological cancers, their application for solid tumor treatment is limited. However, there is strong evidence that combinatorial administration of vorinostat and genotoxic agents (e.g., doxorubicin) enhances the antitumoral action of both drugs against tumors. We developed a high-performance liquid chromatography method for the simultaneous determination of doxorubicin and vorinostat in polymeric nanoparticles designed to provide the parenteral administration of both drugs and increase their safety profile. We performed separation on Nucleodur C-18 Gravity column with a mixture of 10 mM potassium dihydrogen phosphate buffer pH 3.9:ACN (90:10 v/v) as mobile phase at 240 nm. The method was linear within the concentration range of 4.2-52.0 μg/ml for both drugs with limits of detection and quantification of 3.5 and 10.7 μg/ml for doxorubicin and 2.5 and 7.7 μg/ml for vorinostat, respectively. The method was precise and accurate over the concentration range of analysis. Drug loading was 5.4% for doxorubicin and 0.8% for vorinostat. Degradation of doxorubicin after irradiation was less than 5%, while the amount of vorinostat decreased at 88% under the same conditions. Thus, the validated method could be adopted for routine simultaneous analysis of doxorubicin and vorinostat in polymeric nanoparticles.
Topics: Humans; Vorinostat; Chromatography, High Pressure Liquid; Doxorubicin; Histone Deacetylase Inhibitors; Neoplasms; Pharmaceutical Preparations; Nanoparticles
PubMed: 36427291
DOI: 10.1002/jssc.202200731 -
The AAPS Journal Oct 2021Ordinary differential equation (ODE)-based models of signal transduction pathways often contain parameters that are unidentifiable or unmeasurable by experimental data,...
Ordinary differential equation (ODE)-based models of signal transduction pathways often contain parameters that are unidentifiable or unmeasurable by experimental data, and calibrating such models to data remains challenging. Here, two efficient parameter estimation methods, cluster Gauss-Newton (CGN) and CellNOpt (CNO), were applied to fit a signaling network model of U266 multiple myeloma cells to the activity dynamics of key proteins in response to vorinostat and/or bortezomib. A logic-based network model was constructed and transformed to 17 ODEs with 79 parameters estimated within broad ranges of biologically plausible values. The top 10% best-fit parameters by both methods had high uncertainties with CV > 50% for the majority of parameters. The root mean square and prediction errors were comparable without statistically significant differences between the two methods. Despite uncertain parameter estimation, protein dynamics after the sequential combination of bortezomib and vorinostat was predicted with reasonable accuracy and precision. Global sensitivity analyses of partial rank correlation coefficients and Sobol sensitivity demonstrated that apoptosis induction was most sensitive to parameters governing the activity of the proteasome-JNK-caspase-8 axis. Simulations revealed that the greatest magnitude of pharmacodynamic drug interactions between bortezomib and vorinostat occurred at caspase-9, AKT, and Bcl-2. Two sequential combinations were explored in silico, and the outcome matched qualitatively with an empirical evaluation of the pharmacodynamic interaction based on cell viability. Overall, the CGN and CNO algorithms performed similarly for this ODE-based network model calibration, and the calibrated model provided meaningful insights into cellular signaling mechanisms in response to pharmacological perturbations.
Topics: Algorithms; Antineoplastic Agents; Bortezomib; Cell Line, Tumor; Computer Simulation; Drug Interactions; Humans; Models, Theoretical; Multiple Myeloma; Signal Transduction; Vorinostat
PubMed: 34622346
DOI: 10.1208/s12248-021-00640-7 -
Cell Death & Disease May 2018Despite recent progress in the treatment, the outcome of adult acute T-cell lymphoblastic leukemia (T-ALL) is poor. Development of novel approach to combat this disease...
Despite recent progress in the treatment, the outcome of adult acute T-cell lymphoblastic leukemia (T-ALL) is poor. Development of novel approach to combat this disease is urgently required. Vorinostat, a pan-histone deacetylase (HDAC) inhibitor, exerts promising anticancer activity in a variety of solid and hematologic malignancies. However, the efficacy of vorinostat monotherapy is unsatisfactory. Here, we show that quinacrine (QC), an anti-malaria drug with potent autophagy inhibitory activity, could synergistically enhance vorinostat-induced cell death at a non-toxic concentration. Compared to the single treatment, QC plus vorinostat significantly induced apoptosis, disrupted the mitochondrial transmembrane potential, and decreased Mcl-1 and Bcl-2/Bax ratio. Interestingly, the application of QC plus vorinostat resulted in mitophagy blockade, as reflected by the increase in the K63-linked ubiquitination of mitochondria protein and the formation of mitochondrial aggresomes. QC plus vorinostat markedly increased the reactive oxygen species (ROS) level in cells. Moreover, the ROS scavenger N-acetylcysteine (NAC) abrogated QC plus vorinostat-induced ROS, decreased the ubiquitination of mitochondria proteins, and cell death. Finally, using a xenograft mouse model, we demonstrated that QC plus vorinostat significantly reduced cell proliferation and induced cell death in vivo. Taken together, our results showed that the combination of QC with vorinostat may represent a novel regimen for the treatment of T-cell acute lymphoblastic leukemia, which deserves clinical evaluation in the future.
Topics: Animals; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Synergism; Humans; Membrane Potential, Mitochondrial; Mice, Inbred NOD; Mice, SCID; Mitochondria; Mitophagy; Models, Biological; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Quinacrine; Reactive Oxygen Species; Vorinostat
PubMed: 29789603
DOI: 10.1038/s41419-018-0679-6