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Haematologica Jan 2024Tenalisib, a selective phosphoinositide-3-kinase δ/γ, and salt-inducible-kinase-3 inhibitor has shown efficacy and was well-tolerated in patients with T-cell lymphoma...
Safety and efficacy of tenalisib in combination with romidepsin in patients with relapsed/refractory T-cell lymphoma: results from a phase I/II open-label multicenter study.
Tenalisib, a selective phosphoinositide-3-kinase δ/γ, and salt-inducible-kinase-3 inhibitor has shown efficacy and was well-tolerated in patients with T-cell lymphoma (TCL). In vitro studies suggest a synergistic anti-tumor potential for the combination of tenalisib with the histone-deacetylase inhibitor, romidepsin. This multicenter, open-label, phase I/II study was designed to characterize the safety, efficacy and pharmacokinetics of oral tenalisib twice-daily and intravenous romidepsin administered on days 1, 8 and 15 in 28-day cycles in adults with relapsed/refractory TCL. Phase I/dose escalation determined the maximum tolerated dose (MTD)/optimal doses of tenalisib and romidepsin. The phase II/dose expansion assessed the safety and anti-tumor activity of the combination at MTD/optimal dose. Overall, 33 patients were enrolled. In dose escalation, no dose-limiting toxicity was identified. Hence, the recommended doses for dose expansion were tenalisib 800 mg twice daily orally, and romidepsin 14 mg/m2 intravenous. Overall treatment-emergent adverse events of any grade reported in >15% of patients were nausea, thrombocytopenia, increased aspartate aminotransferase, increased alanine aminotransferase, decreased appetite, neutropenia, vomiting, fatigue, anemia, dysgeusia, weight loss, diarrhea, and hypokalemia. Twenty-three patients (69.7%) had related grade ≥3 treatment-emergent adverse events. The overall objective response rate in evaluable patients was 63.0% (peripheral TCL: 75% and cutaneous TCL: 53.3%), with a complete response and partial response of 25.9% and 37.0% respectively. The median duration of response was 5.03 months. Co-administration of tenalisib and romidepsin did not significantly alter the pharmacokinetics of romidepsin. Overall, tenalisib and romidepsin combination demonstrated a favorable safety and efficacy profile supporting its further development for relapsed/refractory TCL (clinicaltrials gov. Identifier: NCT03770000).
Topics: Adult; Humans; Neoplasm Recurrence, Local; Lymphoma, T-Cell; Lymphoma, T-Cell, Peripheral; Skin Neoplasms; Treatment Outcome
PubMed: 37439343
DOI: 10.3324/haematol.2022.281875 -
Critical Reviews in Oncology/hematology Mar 2016Peripheral T-cell lymphomas (PTCLs) tend to be aggressive and chemorefractory, with about 70% of patients developing relapsed/refractory disease. Prior to 2009,... (Review)
Review
Peripheral T-cell lymphomas (PTCLs) tend to be aggressive and chemorefractory, with about 70% of patients developing relapsed/refractory disease. Prior to 2009, chemotherapies were the only options for relapsed/refractory PTCL, other than hematopoietic transplants. However, chemotherapy only improves survival by about 1 month compared with palliation. Four drugs are now approved in the US to treat relapsed/refractory PTCL: pralatrexate, romidepsin, belinostat, and brentuximab vedotin (for systemic anaplastic large cell lymphoma [sALCL]). Response rates with pralatrexate, romidepsin, and belinostat range from 25 to 54% in mixed relapsed/refractory PTCL populations, while 86% of sALCL patients respond to brentuximab vedotin. Here, we critically evaluate the evidence supporting the current drug treatment of relapsed/refractory PTCL, and look to the future to see how the treatment panorama may change with the advent of new targeted therapies, some of which (e.g., alisertib in PTCL and mogamulizumab in CCR4-positive adult T-cell leukemia/lymphoma) are already in phase 3 trials.
Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Drug Resistance, Neoplasm; Humans; Lymphoma, T-Cell, Peripheral; Neoplasm Recurrence, Local; Salvage Therapy
PubMed: 26811013
DOI: 10.1016/j.critrevonc.2015.12.016 -
Clinical Epigenetics Apr 2023Approximately 95% of advanced colorectal cancer patients (CRC) have mismatch repair MMR-proficient (MMRp) tumors, which do not respond to PD1 blockade alone. Preclinical...
BACKGROUND
Approximately 95% of advanced colorectal cancer patients (CRC) have mismatch repair MMR-proficient (MMRp) tumors, which do not respond to PD1 blockade alone. Preclinical studies have shown that combined histone deacetylases (HDAC) and/or DNA methyltransferases (DNMT) inhibition can induce susceptibility to immune checkpoint therapy and inhibit tumor growth. We conducted a pilot trial evaluating PD-1 immune checkpoint inhibitor therapy in combination with DNMT and HDAC inhibitors in MMRp CRC. The study was designed with a biological endpoint of change in immune cell infiltration, to determine the optimal epigenetic combination that optimizes the tumor microenvironment. This trial was designed to test that hypothesis.
RESULTS
From January 2016 to November 2018, 27 patients were enrolled with median age of 57 (range 40-69) years. Median progression-free survival and overall survival were 2.79 months and 9.17, respectively. One patient in Arm C achieved a durable partial response by RECIST criteria, lasting for approximately 19 months. The most common treatment-related hematological adverse events in all arms were anemia (62%), lymphopenia (54%) and thrombocytopenia (35%), and non-hematological AEs were anorexia (65%), nausea (77%), and vomiting (73%).
CONCLUSIONS
The combination of 5-azacitidine and romidepsin with pembrolizumab was safe and tolerable in patients with advanced MMRp CRC, but with a minimal activity. Further mechanistic investigations are needed to understand epigenetic-induced immunologic shift and to expand the potential applicability of checkpoint inhibitors in this setting.
Topics: Humans; Adult; Middle Aged; Aged; DNA Methylation; Colorectal Neoplasms; DNA Modification Methylases; Epigenesis, Genetic; Microsatellite Repeats; Microsatellite Instability; Tumor Microenvironment
PubMed: 37120591
DOI: 10.1186/s13148-023-01485-x -
Immunity, Inflammation and Disease Jan 2023HIV-1 eradication is hindered by the presence of inducible long-lived reservoirs of latently infected cells which rapidly disseminate viral particles upon treatment...
INTRODUCTION
HIV-1 eradication is hindered by the presence of inducible long-lived reservoirs of latently infected cells which rapidly disseminate viral particles upon treatment interruption. Eliminating these reservoirs by the so-called shock and kill strategy represents a crucial concept toward an HIV-1 cure. Several molecules called latency-reversing agents (LRAs) are under intensive investigations to reactivate virus gene expression. These studies are mainly conducted on CD4 T cells where LRAs are well tolerated and did not induce global cellular activation. However, despite their broad spectrum, the putative impact of LRAs on other cellular reservoirs such as macrophages is still ill-defined.
METHODS
We investigated the impact of the protein kinase C (PKC) activator bryostatin-1, bromodomain inhibitor JQ1 and histone deacetylase inhibitor romidepsin used either alone or in combination on human primary monocyte-derived macrophages (MDMs).
RESULTS
We demonstrate that bryostatin-1, JQ1, and romidepsin or their combinations are not toxic at nanomolar concentrations but induce metabolic and morphologic alterations of MDMs. Bryostatin-1 triggered the secretion of pro-inflammatory cytokines, while JQ-1 decreased it. Phagocytosis and endocytosis were modestly impaired upon bryostatin-1 treatment whereas efferocytosis was markedly downregulated by romidepsin. Despite its pro-inflammatory profile, bryostatin-1 did not induce classically activated macrophage markers. Finally, we reveal that conditioned medium from bryostatin-1-treated macrophages did not potentiate its reactivation feature.
CONCLUSIONS
Our study reveals that LRAs can diversely impact basic physiologic features of human primary macrophages and could potentially decrease reactivation of nearby CD4 T cells latently infected with HIV-1. Our observations further stress the need to include different cell populations when assessing HIV-1 cure strategies.
Topics: Humans; Virus Activation; Virus Latency; Bryostatins; CD4-Positive T-Lymphocytes; HIV Infections; HIV Seropositivity; Macrophages
PubMed: 36480653
DOI: 10.1002/iid3.590 -
Medicine in Drug Discovery Oct 2020We propose a new plausible mechanism by mean of which SARS-CoV-2 produces extrapulmonary damages in severe COVID-19 patients. The mechanism consist on the existence of...
We propose a new plausible mechanism by mean of which SARS-CoV-2 produces extrapulmonary damages in severe COVID-19 patients. The mechanism consist on the existence of vulnerable proteins (VPs), which are (i) mainly expressed outside the lungs; (ii) their perturbations is known to produce human diseases; and (iii) can be perturbed directly or indirectly by SARS-CoV-2 proteins. These VPs are perturbed by other proteins, which are: (i) mainly expressed in the lungs, (ii) are targeted directly by SARS-CoV-2 proteins, (iii) can navigate outside the lungs as cargo of extracellular vesicles (EVs); and (iv) can activate VPs via subdiffusive processes inside the target organ. Using bioinformatic tools and mathematical modeling we identifies 26 VPs and their 38 perturbators, which predict extracellular damages in the immunologic endocrine, cardiovascular, circulatory, lymphatic, musculoskeletal, neurologic, dermatologic, hepatic, gastrointestinal, and metabolic systems, as well as in the eyes. The identification of these VPs and their perturbators allow us to identify 27 existing drugs which are candidates to be repurposed for treating extrapulmonary damage in severe COVID-19 patients. After removal of drugs having undesirable drug-drug interactions we select 7 drugs and one natural product: apabetalone, romidepsin, silmitasertib, ozanezumab, procaine, azacitidine, amlexanox, volociximab, and ellagic acid, whose combinations can palliate the organs and systems found to be damaged by COVID-19. We found that at least 4 drugs are needed to treat all the multiorgan damages, for instance: the combination of romidepsin, silmitasertib, apabetalone and azacitidine.
PubMed: 33103107
DOI: 10.1016/j.medidd.2020.100069 -
The Lancet. Microbe Mar 2022The administration of broadly neutralising anti-HIV-1 antibodies before latency reversal could facilitate elimination of HIV-1-infected CD4 T cells. We tested this... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The administration of broadly neutralising anti-HIV-1 antibodies before latency reversal could facilitate elimination of HIV-1-infected CD4 T cells. We tested this concept by combining the broadly neutralising antibody 3BNC117 in combination with the latency-reversing agent romidepsin in people with HIV-1 who were taking suppressive antiretroviral therapy (ART).
METHODS
We did a randomised, open-label, phase 2A trial at three university hospital centres in Denmark, Germany, and the USA. Eligible participants were virologically suppressed adults aged 18-65 years who were infected with HIV-1 and on ART for at least 18 months, with plasma HIV-1 RNA concentrations of less than 50 copies per mL for at least 12 months, and a CD4 T-cell count of greater than 500 cells per μL. Participants were randomly assigned (1:1) to receive 3BNC117 plus romidepsin or romidepsin alone in two cycles. All participants received intravenous infusions of romidepsin (5 mg/m given over 120 min) at weeks 0, 1, and 2 (treatment cycle 1) and weeks 8, 9, and 10 (treatment cycle 2). Those in the 3BNC117 plus romidepsin group received an intravenous infusion of 3BNC117 (30 mg/kg given over 60 min) 2 days before each treatment cycle. An analytic treatment interruption (ATI) of ART was done at week 24 in both groups. Our primary endpoint was time to viral rebound during analytic treatment interruption, which was assessed in all participants who completed both treatment cycles and ATI. We used a log-rank test to compare time to viral rebound during analytic treatment interruption between the two groups. This trial is registered with ClinicalTrials.gov, NCT02850016. It is closed to new participants, and all follow-up is complete.
FINDINGS
Between March 20, 2017, and Aug 14, 2018, 22 people were enrolled and randomly assigned, 11 to the 3BNC117 plus romidepsin group and 11 to the romidepsin group. 19 participants completed both treatment cycles and the ATI: 11 in the 3BNC117 plus romidepsin group and 8 in the romidepsin group. The median time to viral rebound during ATI was 18 days (IQR 14-28) in the 3BNC117 plus romidepsin group and 28 days (21-35) in the romidepsin group B (p=0·0016). Although this difference was significant, prolongation of time to viral rebound was not clinically meaningful in either group. All participants in both groups reported adverse events, but overall the combination of 3BNC117 and romidepsin was safe. Two severe adverse events were observed in the romidepsin group during 48 weeks of follow-up, one of which-increased direct bilirubin-was judged to be related to treatment.
INTERPRETATION
The combination of 3BNC117 and romidepsin was safe but did not delay viral rebound during analytic treatment interruptions in individuals on long-term ART. The results of our trial could serve as a benchmark for further optimisation of HIV-1 curative strategies among people with HIV-1 who are taking suppressive ART.
FUNDING
amfAR, German Center for Infection Research.
Topics: Adult; Depsipeptides; HIV Antibodies; HIV Infections; HIV Seropositivity; HIV-1; Humans; Viral Load
PubMed: 35544074
DOI: 10.1016/S2666-5247(21)00239-1 -
Journal of Virus Eradication Jul 2015The limitations to establishing a viral reservoir facilitated by early cART in children could play a critical role in achieving natural control of viral replication upon... (Review)
Review
The limitations to establishing a viral reservoir facilitated by early cART in children could play a critical role in achieving natural control of viral replication upon discontinuation of cART, which could be defined as 'functional cure'. Viral reservoirs could provide a persistent source of recrudescent viraemia after withdrawal of cART, despite temporary remission of HIV-1 infection, as observed in the 'Mississippi baby'. Intensification of cART has been proposed as a strategy to control residual replication and to diminish the reservoirs. The effects of cART intensification with maraviroc persisted after discontinuation of the drug in HIV-1-infected adults. However, in HIV-1-infected children, the emergence of CXCR4-using variants occurs very early, and the use of CCR5 antagonists in these children as intensification therapy may not be the best alternative. New treatments to eradicate HIV-1 are focused on the activation of viral production from latently infected cells to purge and clear HIV-1 reservoirs. This strategy involves the use of a wide range of small molecules called latency-reversing agents (LRAs). Histone deacetylase inhibitors (HDACi) such as givinostat, belinostat and panobinostat, and class I-selective HDACis that include oxamflatin, NCH-51 and romidepsin, are the most advanced in clinical testing for HIV-1 LRAs. Panobinostat and romidepsin show an efficient reactivation profile in J89GFP cells, a lymphocyte HIV-1 latently infected cell line considered a relevant model to study post-integration HIV-1 latency and reactivation. Clinical trials with panobinostat and romidepsin have been performed in children with other pathologies and it could be reasonable to design a clinical trial using these drugs in combination with cART in HIV-1-infected children.
PubMed: 27482406
DOI: No ID Found -
Communications Biology Jul 2020Viral replication is defined by the cellular microenvironment and one key factor is local oxygen tension, where hypoxia inducible factors (HIFs) regulate the cellular...
Viral replication is defined by the cellular microenvironment and one key factor is local oxygen tension, where hypoxia inducible factors (HIFs) regulate the cellular response to oxygen. Human immunodeficiency virus (HIV) infected cells within secondary lymphoid tissues exist in a low-oxygen or hypoxic environment in vivo. However, the majority of studies on HIV replication and latency are performed under laboratory conditions where HIFs are inactive. We show a role for HIF-2α in restricting HIV transcription via direct binding to the viral promoter. Hypoxia reduced tumor necrosis factor or histone deacetylase inhibitor, Romidepsin, mediated reactivation of HIV and inhibiting HIF signaling-pathways reversed this phenotype. Our data support a model where the low-oxygen environment of the lymph node may suppress HIV replication and promote latency. We identify a mechanism that may contribute to the limited efficacy of latency reversing agents in reactivating HIV and suggest new strategies to control latent HIV-1.
Topics: Basic Helix-Loop-Helix Transcription Factors; Cellular Microenvironment; Flow Cytometry; HIV-1; Humans; Hypoxia; Lymphoid Tissue; Oxygen; Promoter Regions, Genetic; Real-Time Polymerase Chain Reaction; Viral Transcription; Virus Activation; Virus Latency; Virus Replication
PubMed: 32665623
DOI: 10.1038/s42003-020-1103-1 -
Clinical Cancer Research : An Official... Sep 2019Both gain-of-function enhancer of zeste homolog 2 (EZH2) mutations and inactivating histone acetyltransferases mutations, such as CREBBP and EP300, have been implicated...
PURPOSE
Both gain-of-function enhancer of zeste homolog 2 (EZH2) mutations and inactivating histone acetyltransferases mutations, such as CREBBP and EP300, have been implicated in the pathogenesis of germinal center (GC)-derived lymphomas. We hypothesized that direct inhibition of EZH2 and histone deacetyltransferase (HDAC) would be synergistic in GC-derived lymphomas.
EXPERIMENTAL DESIGN
Lymphoma cell lines ( = 21) were exposed to GSK126, an EZH2 inhibitor, and romidepsin, a pan-HDAC inhibitor. Synergy was assessed by excess over bliss. Western blot, mass spectrometry, and coimmunoprecipitation were performed. A SU-DHL-10 xenograft model was utilized to validate findings. Pretreatment RNA-sequencing of cell lines was performed. MetaVIPER analysis was used to infer protein activity.
RESULTS
Exposure to GSK126 and romidepsin demonstrated potent synergy in lymphoma cell lines with EZH2 dysregulation. Combination of romidepsin with other EZH2 inhibitors also demonstrated synergy suggesting a class effect of EZH2 inhibition with romidepsin. Dual inhibition of EZH2 and HDAC led to modulation of acetylation and methylation of H3K27. The synergistic effects of the combination were due to disruption of the PRC2 complex secondary to acetylation of RbAP 46/48. A common basal gene signature was shared among synergistic lymphoma cell lines and was characterized by upregulation in chromatin remodeling genes and transcriptional regulators. This finding was supported by metaVIPER analysis which also revealed that HDAC 1/2 and DNA methyltransferase were associated with EZH2 activation.
CONCLUSIONS
Inhibition of EZH2 and HDAC is synergistic and leads to the dissociation of PRC2 complex. Our findings support the clinical translation of the combination of EZH2 and HDAC inhibition in EZH2 dysregulated lymphomas.
Topics: Acetylation; Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Cell Proliferation; Cell Survival; DNA Methylation; Depsipeptides; Drug Synergism; Enhancer of Zeste Homolog 2 Protein; Epigenesis, Genetic; Female; Histone Deacetylase 1; Histone Deacetylase 2; Histone Deacetylase Inhibitors; Humans; Indoles; Lymphoma; Mice; Mice, SCID; Molecular Targeted Therapy; Pyridones; Random Allocation; Xenograft Model Antitumor Assays
PubMed: 30979734
DOI: 10.1158/1078-0432.CCR-18-3989 -
Molecules (Basel, Switzerland) Dec 2022Cyclic peptides are one of the important chemical groups in the HDAC inhibitor family. Following the success of romidepsin in the clinic, naturally occurring cyclic... (Review)
Review
Cyclic peptides are one of the important chemical groups in the HDAC inhibitor family. Following the success of romidepsin in the clinic, naturally occurring cyclic peptides with a hydrophilic moiety have been intensively studied to test their function as HDAC inhibitors. Azumamides A-E, isolated from , are one of the powerful HDAC inhibitor classes. Structurally, azumamides A-E consist of three -α-amino acids and unnatural β-amino acids such as 3-amino-2-methyl-5-nonenedioic acid-9-amide (Amnna) and 3-amino-2-methyl-5-nonenoic-1,9-diacid (Amnda). Moreover, azumamides have a retro-arrangement peptide backbone, unlike other naturally occurring cyclopeptide HDAC inhibitors, owing to the -configuration of all residues. This review summarizes the currently available synthetic methods of azumamides A-E focusing on the synthesis of β-amino acids and macrocyclization. In addition, we overview the structure-activity relationship of azumamides A-E based on reported analogs. Collectively, this review highlights the potentiality of azumamides A-E as an HDAC inhibitor and provides further developmental insight into naturally occurring cyclic peptides in HDAC inhibition.
Topics: Histone Deacetylase Inhibitors; Structure-Activity Relationship; Peptides, Cyclic; Amino Acids; Hydrophobic and Hydrophilic Interactions
PubMed: 36500529
DOI: 10.3390/molecules27238438