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Clinical Epigenetics Aug 2023Peripheral T-cell lymphomas (PTCLs) are a group of highly aggressive malignancies with generally poor prognoses, and the first-line chemotherapy of PTCL has limited... (Review)
Review
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. Mutation analysis based on next-generation sequencing may advance our understanding of the correlation between epigenetic mutation profiles and relevant targeted therapies. Multitargeted HDACis and HDACi-based prodrugs hold promising futures and offer further directions for drug design.
Topics: Humans; Lymphoma, T-Cell, Peripheral; Histone Deacetylase Inhibitors; DNA Methylation; Antineoplastic Agents; Combined Modality Therapy
PubMed: 37533111
DOI: 10.1186/s13148-023-01531-8 -
EBioMedicine Sep 2023Biomarkers 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...
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.
METHODS
BCN02 was a phase I, open-label, single-arm clinical trial in early-treated, HIV infected individuals. Longitudinal plasma proteomes were analyzed in 11 BCN02 participants, including 8 participants that showed a rapid HIV-1 plasma rebound during a monitored antiretroviral pause (MAP-NC, 'non-controllers') and 3 that remained off ART with sustained plasma viremia <2000 copies/ml (MAP-C, 'controllers'). Inflammatory and neurological proteomes in plasma were evaluated and integration data analysis (viral and neurocognitive parameters) was performed. Validation studies were conducted in a cohort of untreated HIV-1+ individuals (n = 96) and in vitro viral replication assays using an anti-CD33 antibody were used for functional validation.
FINDINGS
Inflammatory plasma proteomes in BCN02 participants showed marked longitudinal alterations. Strong proteome differences were also observed between MAP-C and MAP-NC, including in baseline timepoints. CD33/Siglec-3 was the unique plasma marker with the ability to discriminate between MAPC-C and MAP-NC at all study timepoints and showed positive correlations with viral parameters. Analyses in an untreated cohort of PLWH confirmed the positive correlation between viral parameters and CD33 plasma levels, as well as PBMC gene expression. Finally, adding an anti-CD33 antibody to in vitro virus cultures significantly reduced HIV-1 replication and proviral levels in T cells and macrophages.
INTERPRETATION
This study indicates that CD33/Siglec-3 may serve as a predictor of HIV-1 control and as potential therapeutic tool to improve future cure strategies.
FUNDING
Spanish Science and Innovation Ministry (SAF2017-89726-R and PID2020-119710RB-I00), NIH (P01-AI131568), European Commission (GA101057548) and a Grifols research agreement.
Topics: Humans; CD4-Positive T-Lymphocytes; HIV Infections; HIV Seropositivity; HIV-1; Leukocytes, Mononuclear; Proteome; Proteomics; Sialic Acid Binding Ig-like Lectin 3; Vaccination; Viral Load; Anti-HIV Agents; Biomarkers
PubMed: 37506557
DOI: 10.1016/j.ebiom.2023.104732 -
Human Cell Nov 2023Dermatofibrosarcoma protuberans (DFSP) is a superficial low-grade sarcoma, genetically characterized by a fusion gene in collagen type I α (COL1A1) gene and...
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. The development of definitive chemotherapies for DFSP with fibrosarcomatous transformation is required. Patient-derived tumor cell lines are indispensable tools for preclinical research to discover novel therapeutic agents. However, only seven cell lines were derived from DFSP, out of which only two were established from DFSP with fibrosarcomatous transformation. Hence, in the present study, we established a novel DFSP cell line, NCC-DFSP4-C1, from a surgically resected DFSP tumor specimen with fibrosarcomatous transformation. NCC-DFSP4-C1 harbored an identical COL1A1-PDGFB fusion gene as its donor tumor. NCC-DFSP4-C1 cells retained the morphology of their donor tumor and demonstrated constant proliferation, spheroid formation, and invasion capability in vitro. By screening a drug library, we found that bortezomib and romidepsin demonstrated the strongest suppressive effects on the proliferation of NCC-DFSP4-C1 cells. In conclusion, we report a novel cell line of DFSP with fibrosarcomatous transformation, and demonstrate its utility in the development of novel therapeutic agents for DFSP.
PubMed: 37490236
DOI: 10.1007/s13577-023-00932-4 -
Molecular Therapy. Nucleic Acids Sep 2023Muscle-invasive urothelial cancer (MUC), characterized by high aggressiveness and significant heterogeneity, is currently lacking highly precise individualized treatment...
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. Subsequent screening enabled identification of 12 hub genes that constitute a CMLS with robust predictive power for prognosis. The low-CMLS group exhibited a more favorable prognosis and greater responsiveness to immunotherapy and was more likely to exhibit the "hot tumor" phenotype. The high-CMLS group had a poor prognosis and lower likelihood of benefitting from immunotherapy, but dasatinib and romidepsin may serve as promising treatments for them. Comprehensive analysis of multiomics data can offer important insights and further refine the molecular classification of MUC. Identification of CMLS represents a valuable tool for early prediction of patient prognosis and for screening potential candidates likely to benefit from immunotherapy, with broad implications for clinical practice.
PubMed: 37449047
DOI: 10.1016/j.omtn.2023.06.001 -
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 -
Frontiers in Oncology 2023The overall survival of peripheral T-cell lymphoma (PTCL) is dismal. Histone deacetylase (HDAC) inhibitors have exhibited promising treatment outcomes for PTCL patients....
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.gov, and Cochrane Library database. The pooled overall response rate, complete response (CR) rate, and partial response rate were measured. The risk of adverse events was evaluated. Moreover, the subgroup analysis was utilized to assess the efficacy among different HDAC inhibitors and efficacy in different PTCL subtypes.
RESULTS
For untreated PTCL, 502 patients in seven studies were involved, and the pooled CR rate was 44% (95% , 39-48%). For R/R PTCL patients, there were 16 studies included, and the CR rate was 14% (95% , 11-16%). The HDAC inhibitor-based combination therapy exhibited better efficacy when compared with HDAC inhibitor monotherapy for R/R PTCL patients ( = 0.02). In addition, the pooled CR rate was 17% (95% , 13-22%), 10% (95% , 5-15%), and 10% (95% , 5-15%) in the romidepsin, belinostat, and chidamide monotherapy subgroups, respectively. In the R/R angioimmunoblastic T-cell lymphoma subgroup, the pooled ORR was 44% (95% , 35-53%), higher than other subtypes. A total of 18 studies were involved in the safety assessment of treatment-related adverse events. Thrombocytopenia and nausea were the most common hematological and non-hematological adverse events, respectively.
CONCLUSION
This meta-analysis demonstrated that HDAC inhibitors were effective treatment options for untreated and R/R PTCL patients. The combination of HDAC inhibitor and chemotherapy exhibited superior efficacy to HDAC inhibitor monotherapy in the R/R PTCL setting. Additionally, HDAC inhibitor-based therapy had higher efficacy in angioimmunoblastic T-cell lymphoma patients than that in other subtypes.
PubMed: 37384289
DOI: 10.3389/fonc.2023.1127112 -
ACS Omega Jun 2023Cholangiocarcinoma, also known as biliary tract cancer, is an aggressive adenocarcinoma arising from epithelial cells lining the intra- and extrahepatic biliary system....
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. Combination indexes were calculated using CompuSyn software. Consequently, apoptosis was detected by Annexin V/PI staining. The effect of the drugs on the cell cycle was measured by the propidium iodide staining. The HDAC inhibition was confirmed via acetylated histone protein levels by western blotting. HDAC inhibitors, MS-275 and romidepsin, showed a better synergistic effect with the nocodazole combination. The combination treatment exerted its growth inhibitory effect by cell cycle arrest and induction of apoptosis. The cell cycle analysis of the combination treatment showed that the S phase and G2/M phase were achieved. Moreover, the necrotic and apoptotic cell population increased after single HDAC inhibitors and combination treatment. The anti-cancer effect of HDAC inhibitors is revealed by acetylation levels of histones. While acetylation levels were increased in response to HDAC inhibitors and autophagy modulator combinations, the HDAC expression decreased. This study highlights the importance of the combination of HDAC inhibition and autophagy modulators and demonstrates a synergistic effect, which could be a promising therapy and novel treatment approach for cholangiocarcinoma.
PubMed: 37360445
DOI: 10.1021/acsomega.3c01317 -
Human Cell Sep 2023Giant 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 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. Therefore, this study aimed to establish novel GCTB cell lines and successfully created NCC-GCTB6-C1 and NCC-GCTB7-C1 cell lines from two patients' surgically removed tumor tissues. These cell lines exhibited H3-3A gene mutations, consistent proliferation, and invasive properties. After characterizing their behaviors, we performed high-throughput screening of 214 anti-cancer drugs for NCC-GCTB6-C1 and NCC-GCTB7-C1 and integrated their screening data with those of NCC-GCTB1-C1, NCC-GCTB2-C1, NCC-GCTB3-C1, NCC-GCTB4-C1, and NCC-GCTB5-C1 that we previously established. We identified histone deacetylase inhibitor romidepsin as a possible treatment for GCTB. These findings suggest that NCC-GCTB6-C1 and NCC-GCTB7-C1 could be valuable tools for preclinical and basic research on GCTB.
Topics: Humans; Giant Cell Tumor of Bone; Cell Line, Tumor; Bone Neoplasms; Antineoplastic Agents; Cell Proliferation
PubMed: 37328637
DOI: 10.1007/s13577-023-00928-0 -
Blood Advances Oct 2023Peripheral T-cell lymphomas (PTCLs) are associated with poor prognosis when treated with cytotoxic chemotherapy. We report the findings of a phase 2 study evaluating a...
Peripheral T-cell lymphomas (PTCLs) are 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 patients with PTCL who were aged >60 years or noncandidates for chemotherapy. Treatment was initiated with romidepsin 10 mg/m2 IV on days 1, 8, and 15 and lenalidomide 25 mg taken orally from days 1 to 21 of 28-day cycle for up to 1 year. The primary objective was overall response rate (ORR). Secondary objectives included safety and survival. The study enrolled 29 patients with a median age of 75 years, including 16 (55%) angioimmunoblastic T-cell lymphoma (AITL), 10 (34%) PTCL- not otherwise specified, 2 ATLL, and 1 EATL. Grade 3 to 4 hematologic toxicities included neutropenia (45%), thrombocytopenia (34%), and anemia (28%). Grade 3 to 4 nonhematologic toxicities included hyponatremia (45%), hypertension (38%), hypoalbuminemia (24%), fatigue (17%), hyperglycemia (14%), hypokalemia (14%), dehydration (10%), and infection (10%). At median follow-up of 15.7 months, 23 patients were evaluable and received a median treatment of 6 cycles. The ORR was 65.2% with complete response (CR) at 26.1%, including 78.6% ORR and 35.7% CR for AITL. Median duration of response was 10.7 months, with 27.1 months for patients achieving CR. The estimated 2-year progression-free survival was 31.5%, and 2-year overall survival was 49.5%. This study provides the first demonstration that the biologic combination of romidepsin and lenalidomide is feasible and effective as initial therapy for PTCL and warrants further evaluation. This trial was registered at www.clinicaltrials.gov as #NCT02232516.
Topics: Humans; Aged; Lymphoma, T-Cell, Peripheral; Lenalidomide; Treatment Outcome; Depsipeptides
PubMed: 37327113
DOI: 10.1182/bloodadvances.2023009767 -
International Journal of Cancer Sep 2023BRAF mutations are the most common oncogenic alterations in melanoma cells, supporting proliferation, invasion, metastasis and immune evasion. In patients, these...
Reversing vemurafenib-resistance in primary melanoma cells by combined romidepsin and type I IFN treatment through blocking of tumorigenic signals and induction of immunogenic effects.
BRAF 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). Targeted resequencing revealed that each VEM-resistant melanoma cell line and the parental counterpart are characterized by a distinctive and similar genetic fingerprint, shaping the differential and specific antitumor modulation of MAPK/AKT pathways by combined drug treatment. By using RNA-sequencing and functional in vitro assays, we further report that romidepsin-IFN-α2b treatment restores epigenetically silenced immune signals, modulates MITF and AXL expression and induces both apoptosis and necroptosis in sensitive and VEM-resistant primary melanoma cells. Moreover, the immunogenic potential of drug-treated VEM-resistant melanoma cells results significantly enhanced, given the increased phagocytosis rate of these cells by dendritic cells, which in turn exhibit also a selective down-modulation of the immune checkpoint TIM-3. Overall, our results provide evidence that combined epigenetic-immune drugs can overcome VEM resistance of primary melanoma cells by oncogenic and immune pathways reprogramming, and pave the way for rapidly exploiting this combination to improve BRAFi-resistant metastatic melanoma treatment, also via reinforcement of immune checkpoint inhibitor therapy.
Topics: Humans; Vemurafenib; Drug Resistance, Neoplasm; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Melanoma; Interferon Type I; Cell Line, Tumor
PubMed: 37293858
DOI: 10.1002/ijc.34602