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Magyar Onkologia Mar 2017The therapy of lymphomas has undergone a major expansion during the last decade. Novel therapeutic targets have appeared beyond classical chemotherapeutic combinations.... (Review)
Review
The therapy of lymphomas has undergone a major expansion during the last decade. Novel therapeutic targets have appeared beyond classical chemotherapeutic combinations. These novel drugs have very pronounced action across lymphoma types, and their toxicity profile is usually better tolerable compared to standard chemotherapies. These new therapies are enabling us to offer treatment to those patients who have refractory disease, and we had no option to treat them before these drugs. The author describes several new therapeutic options. New chemotherapeutic drugs are pixantrone and bendamustin. Monoclonal antibodies, like rituximab, ofatumumab, obinotuzumab are described, and conjugated antibodies like brentuximab vedotin and inotuzumab ozogamicin are also discussed. The bispecific antibody blinatumomab can modulate the immune response, and the new class of immune checkpoint inhibitors (pembrolizumab, nivolumab) is also discussed. Therapies targeting the epigenetic regulatory network are also important. Several studies reported promising results of abexinostat, vorinostat, belinostat and panobinostat. The new class of immunomodulatory drugs (imids) is also growing, results with thalidomid and lenalidomid are discussed. The proteasome inhibitors are offering new combinations, with the use of bortezomid, carfilzomib, ixazomib. All these new drugs described above offer to the physician several therapeutic options to better treat patients with lymphoma.
Topics: Antibodies, Monoclonal; Antineoplastic Agents; Humans; Immunologic Factors; Lymphoma; Proteasome Inhibitors
PubMed: 28273193
DOI: No ID Found -
Haematologica May 2017Histone deacetylase inhibitors are members of a class of epigenetic drugs that have proven activity in T-cell malignancies, but little is known about their efficacy in...
Histone deacetylase inhibitors are members of a class of epigenetic drugs that have proven activity in T-cell malignancies, but little is known about their efficacy in B-cell lymphomas. Abexinostat is an orally available hydroxamate-containing histone deacetylase inhibitor that differs from approved inhibitors; its unique pharmacokinetic profile and oral dosing schedule, twice daily four hours apart, allows for continuous exposure at concentrations required to efficiently kill tumor cells. In this phase II study, patients with relapsed/refractory non-Hodgkin lymphoma or chronic lymphocytic leukemia received oral abexinostat at 80 mg BID for 14 days of a 21-day cycle and continued until progressive disease or unacceptable toxicity. A total of 100 patients with B-cell malignancies and T-cell lymphomas were enrolled between October 2011 and July 2014. All patients received at least one dose of study drug. Primary reasons for discontinuation included progressive disease (56%) and adverse events (25%). Grade 3 or over adverse events and any serious adverse events were reported in 88% and 73% of patients, respectively. The most frequently reported grade 3 or over treatment-emergent related adverse events were thrombocytopenia (80%), neutropenia (27%), and anemia (12%). Among the 87 patients evaluable for efficacy, overall response rate was 28% (complete response 5%), with highest responses observed in patients with follicular lymphoma (overall response rate 56%), T-cell lymphoma (overall response rate 40%), and diffuse large B-cell lymphoma (overall response rate 31%). Further investigation of the safety and efficacy of abexinostat in follicular lymphoma, T-cell lymphoma, and diffuse large B-cell lymphoma implementing a less dose-intense week-on-week-off schedule is warranted. ().
Topics: Adult; Aged; Aged, 80 and over; Benzofurans; Diarrhea; Disease-Free Survival; Drug Administration Schedule; Female; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Non-Hodgkin; Male; Middle Aged; Remission Induction; Thrombocytopenia; Treatment Outcome
PubMed: 28126962
DOI: 10.3324/haematol.2016.154377 -
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 -
Stem Cells Translational Medicine Aug 2016: The epigenetic mechanisms promoting lineage-specific commitment of human skeletal (mesenchymal or stromal) stem cells (hMSCs) into adipocytes or osteoblasts are still...
UNLABELLED
: The epigenetic mechanisms promoting lineage-specific commitment of human skeletal (mesenchymal or stromal) stem cells (hMSCs) into adipocytes or osteoblasts are still not fully understood. Herein, we performed an epigenetic library functional screen and identified several novel compounds, including abexinostat, which promoted adipocytic and osteoblastic differentiation of hMSCs. Using gene expression microarrays, chromatin immunoprecipitation for H3K9Ac combined with high-throughput DNA sequencing (ChIP-seq), and bioinformatics, we identified several key genes involved in regulating stem cell proliferation and differentiation that were targeted by abexinostat. Concordantly, ChIP-quantitative polymerase chain reaction revealed marked increase in H3K9Ac epigenetic mark on the promoter region of AdipoQ, FABP4, PPARγ, KLF15, CEBPA, SP7, and ALPL in abexinostat-treated hMSCs. Pharmacological inhibition of focal adhesion kinase (PF-573228) or insulin-like growth factor-1R/insulin receptor (NVP-AEW51) signaling exhibited significant inhibition of abexinostat-mediated adipocytic differentiation, whereas inhibition of WNT (XAV939) or transforming growth factor-β (SB505124) signaling abrogated abexinostat-mediated osteogenic differentiation of hMSCs. Our findings provide insight into the understanding of the relationship between the epigenetic effect of histone deacetylase inhibitors, transcription factors, and differentiation pathways governing adipocyte and osteoblast differentiation. Manipulating such pathways allows a novel use for epigenetic compounds in hMSC-based therapies and tissue engineering.
SIGNIFICANCE
This unbiased epigenetic library functional screen identified several novel compounds, including abexinostat, that promoted adipocytic and osteoblastic differentiation of human skeletal (mesenchymal or stromal) stem cells (hMSCs). These data provide new insight into the understanding of the relationship between the epigenetic effect of histone deacetylase inhibitors, transcription factors, and differentiation pathways controlling adipocyte and osteoblast differentiation of hMSCs. Manipulating such pathways allows a novel use for epigenetic compounds in hMSC-based therapies for tissue engineering, bone disease, obesity, and metabolic-disorders.
Topics: Adipocytes; Adipogenesis; Benzofurans; Cell Differentiation; Cell Line; Cell Lineage; Chromatin Immunoprecipitation; Computational Biology; Epigenesis, Genetic; Gene Expression Profiling; Gene Expression Regulation, Developmental; Gene Library; Genotype; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Mesenchymal Stem Cells; Myoblasts, Skeletal; Oligonucleotide Array Sequence Analysis; Osteoblasts; Osteogenesis; Phenotype; Signal Transduction; Transcription Factors
PubMed: 27194745
DOI: 10.5966/sctm.2015-0331 -
Oncotarget Aug 2017Despite prominent role of radiotherapy in lung cancer management, there is an urgent need for strategies increasing therapeutic efficacy. Reversible epigenetic changes...
Despite prominent role of radiotherapy in lung cancer management, there is an urgent need for strategies increasing therapeutic efficacy. Reversible epigenetic changes are promising targets for combination strategies using HDAC inhibitors (HDACi). Here we evaluated on two NSCLC cell lines, the antitumor effect of abexinostat, a novel pan HDACi combined with irradiation in normoxia and hypoxia, by clonogenic assays, demonstrating that abexinostat enhances radiosensitivity in a time dependent way with mean SER10 between 1.6 and 2.5 for A549 and H460. We found, by immunofluorescence staining, flow cytometry assays and western blotting, in abexinostat treated cells, increasing radio-induced caspase dependent apoptosis and persistent DNA double-strand breaks associated with decreased DNA damage signalling and repair. Interestingly, we demonstrated on nude mice xenografts that abexinostat potentiates tumor growth delay in combined modality treatments associating not only abexinostat and irradiation but also when adding cisplatin. Altogether, our data demonstrate and anti-tumor effect potentiation by abexinostat combined with irradiation in NSCLC. Moreover, our work suggests for the first time to our knowledge promising triple combination opportunities with HDACi, irradiation and cisplatin which deserves further investigations and could be of major interest in the treatment of NSCLC.
PubMed: 28915585
DOI: 10.18632/oncotarget.14813 -
BMC Chemistry Feb 2024Broad-spectrum histone deacetylase inhibitors (HDACi) have excellent anti-tumor effects, such as abexinostat, which was a novel oral HDACi that was widely used in...
Broad-spectrum histone deacetylase inhibitors (HDACi) have excellent anti-tumor effects, such as abexinostat, which was a novel oral HDACi that was widely used in clinical treatment. The purpose of this study was to establish a rapid and reliable method for the detection of abexinostat concentrations in rat plasma using ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). The mobile phase we used was acetonitrile and 0.1% formic acid, and the internal standard (IS) was givinostat. Selective reaction monitoring (SRM) was used for detection with ion transitions at m/z 397.93 → 200.19 for abexinostat and m/z 422.01 → 186.11 for givinostat, respectively. The intra-day and inter-day precision of abexinostat were less than 11.5% and the intra-day and inter-day accuracy ranged from - 10.7% to 9.7% using this method. During the analysis process, the stability of the test sample was reliable. In addition, the recovery and matrix effects of this method were within acceptable limits. Finally, the method presented in this paper enabled accurate and quick determination of abexinostat levels in rat plasma from the pharmacokinetic study following gavage at a dose of 8.0 mg/kg abexinostat.
PubMed: 38378603
DOI: 10.1186/s13065-024-01144-z -
PloS One 2014EBV-related nasopharyngeal carcinomas (NPCs) still raise serious therapeutic problems. The therapeutic potential of the histone-deacetylase (HDAC) inhibitor Abexinostat...
Treatment of nasopharyngeal carcinoma cells with the histone-deacetylase inhibitor abexinostat: cooperative effects with cis-platin and radiotherapy on patient-derived xenografts.
EBV-related nasopharyngeal carcinomas (NPCs) still raise serious therapeutic problems. The therapeutic potential of the histone-deacetylase (HDAC) inhibitor Abexinostat was investigated using 5 preclinical NPC models including 2 patient-derived xenografts (C15 and C17). The cytotoxicity of Abexinostat used either alone or in combination with cis-platin or irradiation was assessed in vitro by MTT and clonogenic assays using 2 EBV-negative (CNE1 and HONE1) and 3 EBV-positive NPC models (C15, C17 and C666-1). Subsequently, the 3 EBV-positive models were used under the form of xenografts to assess the impact of systemic treatments by Abexinostat or combinations of Abexinostat with cis-platin or irradiation. Several cell proteins known to be affected by HDAC inhibitors and the small viral non-coding RNA EBER1 were investigated in the treated tumors. Synergistic cytotoxic effects of Abexinostat combined with cis-platin or irradiation were demonstrated in vitro for each NPC model. When using xenografts, Abexinostat by itself (12.5 mg/kg, BID, 4 days a week for 3 weeks) had significant anti-tumor effects against C17. Cooperative effects with cis-platin (2 mg/kg, IP, at days 3, 10 and 17) and irradiation (1 Gy) were observed for the C15 and C17 xenografts. Simultaneously two types of biological alterations were induced in the tumor tissue, especially in the C17 model: a depletion of the DNA-repair protein RAD51 and a stronger in situ detection of the small viral RNA EBER1. Overall, these results support implementation of phase I/II clinical trials of Abexinostat for the treatment of NPC. A depletion of RAD51 is likely to contribute to the cooperation of Abexinostat with DNA damaging agents. Reduction of RAD51 combined to enhanced detection of EBER 1 might be helpful for early assessment of tumor response.
Topics: Adolescent; Adult; Animals; Antineoplastic Agents; Benzofurans; Carcinoma; Cell Line, Tumor; Cell Survival; Cisplatin; Disease Models, Animal; Drug Synergism; Female; Herpesvirus 4, Human; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Inhibitory Concentration 50; Male; Mice; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; RNA, Viral; Rad51 Recombinase; Tumor Burden; Tumor Stem Cell Assay; Xenograft Model Antitumor Assays
PubMed: 24618637
DOI: 10.1371/journal.pone.0091325 -
Journal of Clinical Oncology : Official... Apr 2017Purpose This phase I trial evaluated epigenetic modulation of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor by using a histone deacetylase...
Inhibiting Histone Deacetylase as a Means to Reverse Resistance to Angiogenesis Inhibitors: Phase I Study of Abexinostat Plus Pazopanib in Advanced Solid Tumor Malignancies.
Purpose This phase I trial evaluated epigenetic modulation of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor by using a histone deacetylase abexinostat in combination with pazopanib to enhance response and reverse resistance. Patients and Methods Pazopanib was administered once a day on days 1 to 28 and abexinostat was administered orally twice a day on days 1 to 5, 8 to 12, and 15 to 19 (schedule A) or on days 1 to 4, 8 to 11, and 15 to 18 (schedule B). Dose escalation (3 + 3 design) in all solid tumors was followed by dose expansion in renal cell carcinoma (RCC). Results Fifty-one patients with RCC (N = 22) were enrolled, including 30 (59%) with one or more lines of prior VEGF-targeting therapy. Five dose-limiting toxicities, including fatigue (n = 2), thrombocytopenia (n = 2), and elevated AST/ALT (n = 1), were observed with schedule A; one dose-limiting toxicity was observed (elevated AST/ALT) was observed with schedule B. Grade ≥ 3 related adverse events included fatigue (16%), thrombocytopenia (16%), and neutropenia (10%). The recommended phase II dose was established as abexinostat 45 mg/m twice a day administered per schedule B plus pazopanib 800 mg/d. Objective response rate was 21% overall and 27% in the RCC subset. Median duration of response was 9.1 months (1.2 to > 49 months). Eight patients (16%) had durable control of disease for > 12 months. Durable tumor regressions were observed in seven (70%) of 10 patients with pazopanib-refractory disease, including one patients with RCC with ongoing response > 3.5 years. Peripheral blood histone acetylation and HDAC2 gene expression were associated with durable response to treatment. Conclusion Abexinostat is well tolerated in combination with pazopanib, allowing prolonged exposure and promising durable responses in pazopanib- and other VEGF inhibitor-refractory tumors, which supports epigenetically mediated reversal of treatment resistance.
Topics: Acetylation; Adult; Aged; Alanine Transaminase; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Aspartate Aminotransferases; Benzofurans; Carcinoma, Renal Cell; Disease Progression; Disease-Free Survival; Drug Resistance; Drug Resistance, Neoplasm; Epigenesis, Genetic; Fatigue; Female; Gene Expression; Histone Deacetylase 2; Histone Deacetylase Inhibitors; Histones; Humans; Hydroxamic Acids; Indazoles; Kidney Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Neutropenia; Pyrimidines; Sulfonamides; Thrombocytopenia; Treatment Outcome; Vascular Endothelial Growth Factor A; Young Adult
PubMed: 28221861
DOI: 10.1200/JCO.2016.70.5350 -
Cancer Apr 2015
Topics: Antibiotics, Antineoplastic; Benzofurans; Doxorubicin; Female; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Male; Sarcoma
PubMed: 25537232
DOI: 10.1002/cncr.29177 -
Cancer Apr 2015It has been demonstrated that several inhibitors of histone deacetylase (HDAC) can enhance chemotherapy-induced apoptosis and reduce sarcoma tumor volume in preclinical...
BACKGROUND
It has been demonstrated that several inhibitors of histone deacetylase (HDAC) can enhance chemotherapy-induced apoptosis and reduce sarcoma tumor volume in preclinical models. The authors sought to determine the maximum tolerated dose, pharmacokinetics/pharmacodynamics, safety, and toxicity of the HDAC inhibitor abexinostat (PCI-24781) when administered with doxorubicin to patients with metastatic sarcomas.
METHODS
Participants were enrolled in a standard, phase 1, 3 + 3, dose-escalation study design. Abexinostat was administered on days 1 through 5 with 75 mg/m(2) of doxorubicin administered on day 4 of every 21-day cycle until patients developed disease progression or drug intolerance or reached a cumulative lifetime doxorubicin dose of 450 mg/m(2). Granulocyte-colony-stimulating factor (G-CSF) support was provided at physician discretion on arm A and was provided to all participants in arm B. From 3 to 6 participants initially received abexinostat 30 mg/m(2) twice daily, and subsequent cohorts were administered doses of 15 mg/m(2), 45 mg/m(2), or 60 mg/m(2) twice daily. All patients without progressive disease after receiving a cumulative lifetime doxorubicin dose of 450 mg/m(2) were given the option to continue with abexinostat as a single agent until they developed disease progression.
RESULTS
In total, 22 participants (10 who had previously experienced tumor growth after doxorubicin therapy) were enrolled (6 in arm A, 14 in arm B), 20 were evaluable for dose-limiting toxicity (DLT), and 17 were evaluable for radiologic response. In arm A, participants received abexinostat 15 mg/m(2) or 30 mg/m(2) twice daily. DLTs of grade 3 and 4 neutropenia were observed in 2 of 3 participants who received abexinostat 30 mg/m(2) twice daily. Neither of those patients received G-CSF prophylaxis. In arm B, participants received abexinostat at doses of 30 mg/m(2), 45 mg/m(2), or 60 mg/m(2) twice daily, all with mandated G-CSF support. Two DLTs were observed at the 60 mg/m(2) twice-daily dose (grade 3 infection, grade 4 thrombocytopenia). The pharmacokinetics of abexinostat were not affected by doxorubicin. HDAC activity, as measured by histone acetylation in peripheral blood mononuclear cells, was maximally inhibited at the abexinostat 30 mg/m(2) twice-daily dose. Of the 17 participants who were evaluable for radiologic response, 1 patient had a partial response, 9 patients had stable disease, and 7 patients had progressive disease as their best response; and 8 patients completed ≥ 5 cycles. Three of those participants had stable disease as their most recent disease status when the current report was written. Four participants who continued on monotherapy remained in stable disease for a median of 9.8 weeks after completing doxorubicin. The most common toxicities were fatigue, thrombocytopenia, and anemia. No study-related deaths were observed.
CONCLUSIONS
The maximum tolerated dose for abexinostat was 45 mg/m(2) twice daily administered on days 1 through 5 when patients received doxorubicin 75 mg/m(2) on day 4 of a 3-week cycle and G-CSF support was mandated. Toxicities were manageable, and tumor responses were observed. Additional studies are needed to further define the specific contributions of HDAC inhibition in patients who receive doxorubicin for the treatment of metastatic sarcoma.
Topics: Administration, Oral; Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Benzofurans; Doxorubicin; Drug Administration Schedule; Female; Granulocyte Colony-Stimulating Factor; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Male; Maximum Tolerated Dose; Middle Aged; Sarcoma; Treatment Outcome; Young Adult
PubMed: 25536954
DOI: 10.1002/cncr.29175