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Blood Oct 2023This phase 1 study evaluated the addition of vorinostat to pembrolizumab in patients with relapsed/refractory (RR) classical Hodgkin lymphoma (cHL), diffuse large B-cell...
This phase 1 study evaluated the addition of vorinostat to pembrolizumab in patients with relapsed/refractory (RR) classical Hodgkin lymphoma (cHL), diffuse large B-cell lymphoma, and follicular lymphoma. We report the results in cases of cHL. Adult patients with RR cHL who had received ≥1 prior lines of therapy and were ineligible for transplantation were treated in a dose-escalation cohort with 2 dose levels (DLs) and then on an expansion cohort at the recommended phase 2 dose (RP2D) in 21-day cycles. Vorinostat 100 mg twice a day (DL1) and 200 mg twice a day (DL2) was administered orally from days 1 to 5 and 8 to 12; all patients received pembrolizumab 200 mg IV every 3 weeks. The primary end point was safety and determination of RP2D. In total, 32 patients with cHL were enrolled, including 30 at DL2 (RP2D); 78% had received prior anti-programmed cell death 1 (anti-PD-1) therapy, and 56% were PD-1 refractory. Grade ≥3 adverse events (AEs) included hypertension (9%), neutropenia (9%), hypophosphatemia (9%), thrombocytopenia (6%), and lymphopenia (6%). Immune-related AEs included grade 1 or 2 thyroiditis (13%), grade 1 rash (6%), and grade 3 esophagitis/duodenitis (3%). The overall response rate (ORR) was 72% and complete response (CR) rate was 34%. Patients refractory to prior PD-1 blockade (n = 18) had ORR and CR rates of 56% and 11%, respectively. Pembrolizumab and vorinostat was well tolerated with a high ORR rate in RR cHL including in anti-PD-1-refractory disease. This trial was registered at www.clinicaltrials.gov as #NCT03150329.
Topics: Adult; Humans; Hodgkin Disease; Vorinostat; Programmed Cell Death 1 Receptor; Neoplasm Recurrence, Local; Antibodies, Monoclonal, Humanized
PubMed: 37339586
DOI: 10.1182/blood.2023020485 -
European Review For Medical and... Feb 2023Breast cancer (BC) is the most common type of cancer in females worldwide. Various approaches were proposed to treat the disease, with no sole agent proved efficient....
OBJECTIVE
Breast cancer (BC) is the most common type of cancer in females worldwide. Various approaches were proposed to treat the disease, with no sole agent proved efficient. Thus, understanding the molecular mechanisms of different drugs became mandatory. The present study aimed at evaluating the role of erlotinib (ERL) and vorinostat (SAHA) in inducing apoptosis in breast cancer cells. The role of these drugs was assessed also on the expression profile of some cancer-related genes; PTEN, P21, TGF, and CDH1.
MATERIALS AND METHODS
In the present study, breast cancer cells (MCF-7) and MDA-MB-231 along with human amniotic cells (WISH) were treated with two concentrations (50, and 100 µM) of erlotinib (ERL) and vorinostat (as known as SAHA) for 24 h. Cells were harvested for downstream analysis. DNA content and apoptosis were analyzed by flow cytometer, and qPCR was performed to assess the expression of different cancer-related genes.
RESULTS
The results indicated that ERL and SAHA arrested both breast cancer cells at the G2/M phase after 24 h compared to normal cells and control. For apoptosis, BC cells showed an elevated level of total apoptosis (early and late) increasing the concentrations of the two applied drugs, with the most effective concentration of ERL at 100 µM in the 24-h treatment. In the control cells, SAHA was proved to be the most effective drug at a concentration of 100 µM with a percentage of apoptosis ranging from 1.7-12% in the 24-h treatment. Necrosis also was dose-dependent in the two breast cancer cell lines used. We further evaluated the expression profiles of PTEN, P21, TGF-β, and CDH1. In MCF-7, data indicated that for TGF-β, PTEN, and P21, the most effective treatment was SAHA at a concentration of 100 µM, while for CDH1, the most effective concentration was ERL at 100 µM. A similar profile was observed in MDA-MB-232, where for TGF-β, PTEN, and P21, the most effective treatment was SAHA at a concentration of 100 µM, while for CDH1, the most effective concentration was SAHA at 50 µM.
CONCLUSIONS
Our results shed some light on the role of ERL and SAHA in regulating the expression of cancer-related genes, though these data need further investigation.
Topics: Female; Humans; Erlotinib Hydrochloride; PTEN Phosphohydrolase; Transcriptional Activation; Up-Regulation; Vorinostat; Breast Neoplasms; Cell Line, Tumor; Cell Cycle Checkpoints
PubMed: 36876690
DOI: 10.26355/eurrev_202302_31391 -
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 -
AIDS (London, England) Jan 2022The aim of this study was to examine whether administering both vorinostat and disulfiram to people with HIV (PWH) on antiretroviral therapy (ART) is well tolerated and...
OBJECTIVE
The aim of this study was to examine whether administering both vorinostat and disulfiram to people with HIV (PWH) on antiretroviral therapy (ART) is well tolerated and can enhance HIV latency reversal.
DESIGN
Vorinostat and disulfiram can increase HIV transcription in PWH on ART. Together, these agents may lead to significant HIV latency reversal.
METHODS
Virologically suppressed PWH on ART received disulfiram 2000 mg daily for 28 days and vorinostat 400 mg daily on days 8-10 and 22-24. The primary endpoint was plasma HIV RNA on day 11 relative to baseline using a single copy assay. Assessments included cell-associated unspliced RNA as a marker of latency reversal, HIV DNA in CD4+ T-cells, plasma HIV RNA, and plasma concentrations of ART, vorinostat, and disulfiram.
RESULTS
The first two participants (P1 and P2) experienced grade 3 neurotoxicity leading to trial suspension. After 24 days, P1 presented with confusion, lethargy, and ataxia having stopped disulfiram and ART. Symptoms resolved by day 29. After 11 days, P2 presented with paranoia, emotional lability, lethargy, ataxia, and study drugs were ceased. Symptoms resolved by day 23. CA-US RNA increased by 1.4-fold and 1.3-fold for P1 and P2 respectively. Plasma HIV RNA was detectable from day 8 to 37 (peak 81 copies ml-1) for P2 but was not increased in P1 Antiretroviral levels were therapeutic and neuronal injury markers were elevated in P1.
CONCLUSION
The combination of prolonged high-dose disulfiram and vorinostat was not safe in PWH on ART and should not be pursued despite evidence of latency reversal.
Topics: Disulfiram; Drug Therapy, Combination; HIV Infections; Humans; Virus Latency; Vorinostat
PubMed: 34586085
DOI: 10.1097/QAD.0000000000003091 -
Journal of Nuclear Medicine : Official... Jun 2023α-particle emitters have recently been explored as valuable therapeutic radionuclides. Yet, toxicity to healthy organs and cancer radioresistance limit the efficacy of...
Signaling Network Response to α-Particle-Targeted Therapy with the Ac-Labeled Minigastrin Analog Ac-PP-F11N Reveals the Radiosensitizing Potential of Histone Deacetylase Inhibitors.
α-particle emitters have recently been explored as valuable therapeutic radionuclides. Yet, toxicity to healthy organs and cancer radioresistance limit the efficacy of targeted α-particle therapy (TAT). Identification of the radiation-activated mechanisms that drive cancer cell survival provides opportunities to develop new points for therapeutic interference to improve the efficacy and safety of TAT. Quantitative phosphoproteomics and matching proteomics followed by the bioinformatics analysis were used to identify alterations in the signaling networks in response to TAT with the Ac-labeled minigastrin analog Ac-PP-F11N (DOTA-(dGlu)-Ala-Tyr-Gly-Trp-Nle-Asp-Phe) in A431 cells, which overexpress cholecystokinin B receptor (CCKBR). Western blot analysis and microscopy verified the activation of the selected signaling pathways. Small-molecule inhibitors were used to validate the potential of the radiosensitizing combinatory treatments both in vitro and in A431/CCKBR tumor-bearing nude mice. TAT-induced alterations were involved in DNA damage response, cell cycle regulation, and signal transduction, as well as RNA transcription and processing, cell morphology, and transport. Western blot analysis and microscopy confirmed increased phosphorylations of the key proteins involved in DNA damage response and carcinogenesis, including p53, p53 binding protein 1 (p53BP1), histone deacetylases (HDACs), and H2AX. Inhibition of HDAC class II, ataxia-telangiectasia mutated (ATM), and p38 kinases by TMP269, AZD1390, and SB202190, respectively, sensitized A431/CCKBR cells to Ac-PP-F11N. As compared with the control and monotherapies, the combination of Ac-PP-F11N with the HDAC inhibitor vorinostat (suberoylanilide hydroxamic acid, SAHA) significantly reduced the viability and increased the DNA damage of A431/CCKBR cells, led to the most pronounced tumor growth inhibition, and extended the mean survival of A431/CCKBR xenografted nude mice. Our study revealed the cellular responses to TAT and demonstrated the radiosensitizing potential of HDAC inhibitors to Ac-PP-F11N in CCKBR-positive tumors. This proof-of-concept study recommends development of novel radiosensitizing strategies by targeting TAT-activated and survival-promoting signaling pathways.
Topics: Animals; Mice; Histone Deacetylase Inhibitors; Mice, Nude; Tumor Suppressor Protein p53; Cell Line, Tumor; Vorinostat; Signal Transduction; Hydroxamic Acids
PubMed: 36732057
DOI: 10.2967/jnumed.122.264597 -
The Journal of Infectious Diseases Nov 2023Cryptosporidiosis is a significant diarrheal disease in humans and animals. Immunodeficient mice are the primary small animal models, but their high costs and...
BACKGROUND
Cryptosporidiosis is a significant diarrheal disease in humans and animals. Immunodeficient mice are the primary small animal models, but their high costs and specialized breeding/housing requirements limit in vivo drug testing. Numerous anticryptosporidial lead compounds identified in vitro remain untested in vivo.
METHODS
Cryptosporidium tyzzeri, a natural mouse parasite closely related to Cryptosporidium parvum and Cryptosporidium hominis, was isolated to establish an infection model in immunocompetent mice. The model was validated using classic anticryptosporidial drugs (paromomycin and nitazoxanide) and then employed to assess the efficacy of 3 new leads (vorinostat, docetaxel, and baicalein). An in vitro culture of C. tyzzeri was also developed to complement the animal model.
RESULTS
Chronic C. tyzzeri infection was established in chemically immunosuppressed wild-type mice. Paromomycin (1000 mg/kg/d) and nitazoxanide (100 mg/kg/d) demonstrated efficacy against C. tyzzeri. Vorinostat (30 mg/kg/d), docetaxel (25 mg/kg/d), and baicalein (50 mg/kg/d) were highly effective against C. tyzzeri infection. In vitro, nitazoxanide, vorinostat, docetaxel, and baicalein exhibited low to submicromolar efficacy against C. tyzzeri.
CONCLUSIONS
Novel in vivo and in vitro models have been developed for cost-effective anticryptosporidial drug testing. Vorinostat, docetaxel, and baicalein show potential for repurposing and/or optimization for developing new anticryptosporidial drugs.
Topics: Animals; Mice; Humans; Paromomycin; Cryptosporidiosis; Vorinostat; Antiprotozoal Agents; Docetaxel; Cryptosporidium; Cost-Benefit Analysis; Plant Breeding; Cryptosporidium parvum
PubMed: 37418629
DOI: 10.1093/infdis/jiad243 -
Biomedicine & Pharmacotherapy =... May 2023Endometriosis is a common disease in women and may be one of the factors that induces malignant epithelial ovarian tumors. Previous studies suggested that endometriosis...
Endometriosis is a common disease in women and may be one of the factors that induces malignant epithelial ovarian tumors. Previous studies suggested that endometriosis is related to ARID1A mutation mediating the expression of HDAC6, but the detailed pathogenic mechanism is still unclear. First, we collected endometriosis-associated ovarian carcinoma (EAOC) clinical samples and examined the expression of HDAC6. Our results found that the high HDAC6 expression group was positively correlated with EAOC histology (P = 0.015), stage (P < 0.000), and tumor size (P < 0.000) and inversely correlated with survival (P < 0.000). We also found that ARID1A/HDAC6 induced M2 polarization of macrophages through IL-10. In addition, the HDAC inhibitor (HDACi) vorinostat inhibited cell growth and blocked the effect of HDAC6. Tomographic microscopy was used to monitor the live cell morphology of these treated cells, and we found that vorinostat treatment resulted in substantial cell apoptosis by 3 h 42 min. Next, we established a transgenic mouse model of EAOC and found that vorinostat significantly reduced the size of ovarian tumors by inhibiting M2 macrophage polarization in mice. Together, these data demonstrate that the signaling pathway of E4F1/ARID1A/HDAC6/GATA3 mediates macrophage polarization and provides a novel immune cell-associated therapeutic strategy targeting IL-10 in EAOC.
Topics: Humans; Female; Animals; Mice; Vorinostat; Endometriosis; Interleukin-10; Ovarian Neoplasms; Carcinoma, Ovarian Epithelial; Carcinoma; Signal Transduction; Macrophages; DNA-Binding Proteins; Transcription Factors; Histone Deacetylase 6; Repressor Proteins
PubMed: 36958195
DOI: 10.1016/j.biopha.2023.114500 -
Frontiers in Immunology 2023Breast cancer is one of the common malignancies with poor prognosis worldwide. The treatment of breast cancer patients includes surgery, radiation, hormone therapy,... (Review)
Review
Breast cancer is one of the common malignancies with poor prognosis worldwide. The treatment of breast cancer patients includes surgery, radiation, hormone therapy, chemotherapy, targeted drug therapy and immunotherapy. In recent years, immunotherapy has potentiated the survival of certain breast cancer patients; however, primary resistance or acquired resistance attenuate the therapeutic outcomes. Histone acetyltransferases induce histone acetylation on lysine residues, which can be reversed by histone deacetylases (HDACs). Dysregulation of HDACs mutation and abnormal expression contributes to tumorigenesis and tumor progression. Numerous HDAC inhibitors have been developed and exhibited the potent anti-tumor activity in a variety of cancers, including breast cancer. HDAC inhibitors ameliorated immunotherapeutic efficacy in cancer patients. In this review, we discuss the anti-tumor activity of HDAC inhibitors in breast cancer, including dacinostat, belinostat, abexinostat, mocetinotat, panobinostat, romidepsin, entinostat, vorinostat, pracinostat, tubastatin A, trichostatin A, and tucidinostat. Moreover, we uncover the mechanisms of HDAC inhibitors in improving immunotherapy in breast cancer. Furthermore, we highlight that HDAC inhibitors might be potent agents to potentiate immunotherapy in breast cancer.
Topics: Humans; Female; Histone Deacetylases; Histone Deacetylase Inhibitors; Breast Neoplasms; Vorinostat; Immunotherapy
PubMed: 36969235
DOI: 10.3389/fimmu.2023.1164514 -
British Journal of Haematology Sep 2019
Topics: Adult; B-Lymphocytes; Cladribine; Epigenesis, Genetic; Humans; Lymphoma, Mantle-Cell; Rituximab; Vorinostat
PubMed: 31489625
DOI: 10.1111/bjh.16192 -
Gene Nov 2023The role of histone deacetylases (HDACs) in the tumor immune microenvironment of gynecologic tumors remains unexplored. We integrated data from The Cancer Genome Atlas...
The role of histone deacetylases (HDACs) in the tumor immune microenvironment of gynecologic tumors remains unexplored. We integrated data from The Cancer Genome Atlas and Human Protein Atlas to examine HDAC expression in breast, cervical, ovarian, and endometrial cancers. Elevated HDAC expression correlated with poor prognosis and highly malignant cancer subtypes. Gene Set Enrichment Analysis revealed positive associations between HDAC expression and tumor proliferation signature, while negative associations were found with tumor inflammation signature. Increased HDAC expression was linked to reduced infiltration of natural killer (NK), NKT, and CD8 T cells, along with negative associations with the expression of PSMB10, NKG7, CCL5, CD27, HLA-DQA1, and HLA-DQB1. In a murine 4T1 breast cancer model, treatment with suberoylanilide hydroxamic acid (SAHA; HDAC inhibitor) and PD-1 antibody significantly inhibited tumor growth and infiltration of CD3 and CD8 T cells. Real-time polymerase chain reaction revealed upregulated expressions of Psmb10, Nkg7, Ccl5, Cd8a, Cxcr6, and Cxcl9 genes, while Ctnnb1 and Myc genes were inhibited, indicating tumor suppression and immune microenvironment activation. Our study revealed that HDACs play tumor-promoting and immunosuppressive roles in gynecologic cancers, suggesting HDAC inhibitors as potential therapeutic agents for these cancers.
Topics: Female; Humans; Animals; Mice; Histone Deacetylases; Genital Neoplasms, Female; Hydroxamic Acids; CD8-Positive T-Lymphocytes; Vorinostat; Histone Deacetylase Inhibitors; Tumor Microenvironment; Membrane Proteins; Proteasome Endopeptidase Complex
PubMed: 37572797
DOI: 10.1016/j.gene.2023.147704