romidepsin

Since commencing my role as a professor in a newly established Department of Pharmacodynamics and Molecular Genetics at the School of Pharmacy, Iwate Medical University, on April 1, 2007, my research has focused on modifying gene expression of cytochrome P-450 (CYP) in established human colon cancer cells. Additionally, I have been investigating methods to enhance the anti-tumor effects of irinotecan (CPT-11) and 5-fluorouracil (5-FU) using epigenetic modifying inhibitors of DNA methyltransferase and histone deacetylase...

Extraskeletal osteosarcoma (ESOS) is a rare malignant mesenchymal tumor that originates in the soft tissue. ESOS accounts for less than 1% of all soft tissue sarcomas and exhibits an aggressive behavior with a high propensity for local recurrence and distant metastasis. Despite advances in treatment, the prognosis for ESOS remains poor, with a five-year survival rate of less than 50% and 27% for metastatic patients. Ex vivo models derived from patient samples are critical tools for studying rare diseases with poor prognoses, such as ESOS, and identifying potential new treatment strategies...

Leiomyosarcoma (LMS) is an aggressive mesenchymal malignancy, which originates from the smooth muscle cells or from the precursor mesenchymal stem cells that potentially differentiate into smooth muscle cells. LMS is one of the most common sarcomas. LMS has genomic instability, reflecting complex and unbalanced karyotypes, and the cytogenetic and molecular changes in LMS are not consistent. The standard treatment of the primary LMS is complete resection, and the metastasis is often observed even after curative surgery...

Diabetic painful neuropathy (DPN) is one of the most detrimental complications of diabetes. Alterations in neuroinflammatory mediators play significant roles in the development of DPN. Infiltration of the neutrophils and monocyte/macrophages contributes substantial role in the degenerative process of the distal sciatic nerve by forming neutrophil extracellular traps (NETs) under diabetic condition. Citrullination of histones due to increase in protein arginine deiminase (PAD) enzyme activity under hyperglycemia may promote NET formation, which can further increase the cytokine production by activating macrophages and proliferation of neutrophils...

Multiple myeloma (MM) is a hematological malignancy. It is widely believed that genetic factors play a significant role in the development of MM, as investigated in numerous studies. However, the application of genomic information for clinical purposes, including diagnostic and prognostic biomarkers, remains largely confined to research. In this study, we utilized genetic information from the Genomic-Driven Clinical Implementation for Multiple Myeloma database, which is dedicated to clinical trial studies on MM...

Bacterial natural products have found many important industrial applications. Yet traditional discovery pipelines often prioritize individual natural product families despite the presence of multiple natural product biosynthetic gene clusters in each bacterial genome. Systematic characterization of talented strains is a means to expand the known natural product space. Here, we report genomics, epigenomics, and metabolomics studies of Burkholderia sp. FERM BP-3421, a soil isolate and known producer of antitumor spliceostatins...

INTRODUCTION: Understanding the clinical potency of latency-reversing agents (LRAs) on the HIV-1 reservoir is useful to deploy future strategies. This systematic review evaluated the effects of LRAs in human intervention studies. METHODS: A literature search was performed using medical databases focusing on studies with adults living with HIV-1 receiving LRAs. Eligibility criteria required participants from prospective clinical studies, a studied compound hypothesised as LRA, and reactivation or tolerability assessments...

Constitutional mismatch repair deficiency (CMMRD) is a cancer predisposition syndrome associated with the development of hypermutant pediatric high-grade glioma, and confers a poor prognosis. While therapeutic histone deacetylase (HDAC) inhibition of diffuse intrinsic pontine glioma (DIPG) has been reported; here, we use a clinically relevant biopsy-derived hypermutant DIPG model (PBT-24FH) and a CRISPR-Cas9 induced genetic model to evaluate the efficacy of HDAC inhibition against hypermutant DIPG. We screened PBT-24FH cells for sensitivity to a panel of HDAC inhibitors (HDACis) in vitro, identifying two HDACis associated with low nanomolar IC50s, quisinostat (27 nM) and romidepsin (2 nM)...

Cancer metastasis increases the complexity of the disease and escalates patient mortality. Traditional chemotherapy has been associated with low efficacy and marked side effects. Studies pivot toward histone deacetylase (HDAC) enzymes and inhibitors because they are critical for chromatin structure, gene regulation, and cellular activities that are linked to metastasis and cancer progression. HDAC inhibitors (HDACi) can alter gene expression patterns and can lead to cell-cycle arrest and apoptosis in neoplastic cells...

Peripheral T-cell lymphomas (PTCLs) are a group of highly aggressive malignancies with generally poor prognoses, and the first-line chemotherapy of PTCL has limited efficacy. Currently, several novel targeted agents, including histone deacetylase inhibitors (HDACis), have been investigated to improve the therapeutic outcome of PTCLs. Several HDACis, such as romidepsin, belinostat, and chidamide, have demonstrated favorable clinical efficacy and safety in PTCLs. More novel HDACis and new combination therapies are undergoing preclinical or clinical trials...

BACKGROUND: Biomarkers predicting the outcome of HIV-1 virus control in natural infection and after therapeutic interventions in HIV-1 cure trials remain poorly defined. The BCN02 trial (NCT02616874), combined a T-cell vaccine with romidepsin (RMD), a cancer-drug that was used to promote HIV-1 latency reversal and which has also been shown to have beneficial effects on neurofunction. We conducted longitudinal plasma proteomics analyses in trial participants to define biomarkers associated with virus control during monitored antiretroviral pause (MAP) and to identify novel therapeutic targets that can improve future cure strategies...

Dermatofibrosarcoma protuberans (DFSP) is a superficial low-grade sarcoma, genetically characterized by a fusion gene in collagen type I α (COL1A1) gene and platelet-derived growth factor subunit β (PDGFB). DFSP is locally aggressive and does not typically metastasize. However, DFSP with fibrosarcomatous transformation, which occurs in 7-16% of DFSP cases, demonstrates a poor prognosis than classic DFSP with a higher local recurrence rate and metastatic potential. Although imatinib, a PDGF receptor inhibitor, is a potent therapeutic agent for classic DFSP, it is less effective for DFSP with fibrosarcomatous transformation...

Muscle-invasive urothelial cancer (MUC), characterized by high aggressiveness and significant heterogeneity, is currently lacking highly precise individualized treatment options. We used a computational pipeline to synthesize multiomics data from MUC patients using 10 clustering algorithms, which were then combined with 10 machine learning algorithms to identify molecular subgroups of high resolution and develop a robust consensus machine learning-driven signature (CMLS). Through multiomics clustering, we identified three cancer subtypes (CSs) that are related to prognosis, with CS2 exhibiting the most favorable prognostic outcome...

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 twicedaily (BID) and intravenous (IV) romidepsin administered on Days 1, 8 and 15 in 28-day cycles in adults with relapsed/refractory TCL...

BACKGROUND: The overall survival of peripheral T-cell lymphoma (PTCL) is dismal. Histone deacetylase (HDAC) inhibitors have exhibited promising treatment outcomes for PTCL patients. Therefore, this work aims to systematically evaluate the treatment outcome and safety profile of HDAC inhibitor-based treatment for untreated and relapsed/refractory (R/R) PTCL patients. METHODS: The prospective clinical trials of HDAC inhibitors for the treatment of PTCL were searched on the Web of Science, PubMed, Embase, ClinicalTrials...

Cholangiocarcinoma, also known as biliary tract cancer, is an aggressive adenocarcinoma arising from epithelial cells lining the intra- and extrahepatic biliary system. The effects of autophagy modulators and histone deacetylase (HDAC) inhibitors in cholangiocarcinoma are not fully known. It is essential to understand the molecular mechanisms and the effects of HDAC inhibitors in the context of cholangiocarcinoma. The antiproliferative effect of different HDAC inhibitors and autophagy modulation was investigated by the MTT cell viability assay in TFK-1 and EGI-1 cholangiocarcinoma cell lines...

Giant cell tumor of bone (GCTB) is a rare bone tumor with osteolytic features, composed of stromal cells with a monotonous appearance, macrophages, and osteoclast-like giant cells. GCTB is commonly associated with a pathogenic mutation in the H3-3A gene. While complete surgical resection is the standard cure for GCTB, it often results in local recurrence and, rarely, metastasis. Thus, an effective multidisciplinary treatment approach is necessary. Although patient-derived cell lines is an essential tool for investigating novel treatment strategies, there are only four GCTB cell lines available in public cell banks...

PTCL are aggressive malignancies associated with poor prognosis when treated with cytotoxic chemotherapy. We report the findings of a phase 2 study evaluating a chemotherapy-free combination of romidepsin plus lenalidomide as initial treatment for PTCL patients who were over 60 years of age or noncandidates for standard induction chemotherapy (ClinicalTrials.gov-NCT02232516). Treatment was initiated with romidepsin 10 mg/m2 IV on d 1, 8, 15, and lenalidomide 25 mg PO on d 1-21 of 28-day cycle for up to 1 year...

BRAFV600 mutations are the most common oncogenic alterations in melanoma cells, supporting proliferation, invasion, metastasis and immune evasion. In patients, these aberrantly activated cellular pathways are inhibited by BRAFi whose potent antitumor effect and therapeutic potential are dampened by the development of resistance. Here, by using primary melanoma cell lines, generated from lymph node lesions of metastatic patients, we show that the combination of two FDA-approved drugs, the histone deacetylate inhibitor (HDCAi) romidepsin and the immunomodulatory agent IFN-α2b, reduces melanoma proliferation, long-term survival and invasiveness and overcomes acquired resistance to the BRAFi vemurafenib (VEM)...

Immunotherapy based on immune checkpoint inhibitors (ICIs) has revolutionized treatment strategies in multiple types of cancer. However, the resistance and relapse as associated with the extreme complexity of cancer-immunity interactions remain a major challenge to be resolved. Owing to the epigenome plasticity of cancer and immune cells, a growing body of evidence has been presented indicating that epigenetic treatments have the potential to overcome current limitations of immunotherapy, thus providing a rationalefor the combination of ICIs with epigenetic agents (epidrugs)...