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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 -
International Immunopharmacology Jul 2023Immunotherapy based on immune checkpoint inhibitors (ICIs) has revolutionized treatment strategies in multiple types of cancer. However, the resistance and relapse as... (Review)
Review
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). In this review, we first make an overview about the epigenetic regulations in tumor biology and immunodevelopment. Subsequently, a diverse array of inhibitory agents under investigations targeted epigenetic modulators (Azacitidine, Decitabine, Vorinostat, Romidepsin, Belinostat, Panobinostat, Tazemetostat, Enasidenib and Ivosidenib, etc.) and immune checkpoints (Atezolizmab, Avelumab, Cemiplimab, Durvalumb, Ipilimumab, Nivolumab and Pembrolizmab, etc.) to increase anticancer responses were described and the potential mechanisms were further discussed. Finally, we summarize the findings of clinical trials and provide a perspective for future clinical studies directed at investigating the combination of epidrugs with ICIs as a treatment for cancer.
Topics: Humans; Immune Checkpoint Inhibitors; Neoplasms; Nivolumab; Ipilimumab; Immunotherapy
PubMed: 37276826
DOI: 10.1016/j.intimp.2023.110417 -
Cancers Oct 2020Novel treatment options are needed for testicular germ cell tumor (TGCT) patients, particularly important for those showing or developing cisplatin resistance, the major...
Novel treatment options are needed for testicular germ cell tumor (TGCT) patients, particularly important for those showing or developing cisplatin resistance, the major cause of cancer-related deaths. As TGCTs pathobiology is highly related to epigenetic (de)regulation, epidrugs are potentially effective therapies. Hence, we sought to explore, for the first time, the effect of the two most recently FDA-approved HDAC inhibitors (HDACis), belinostat and panobinostat, in (T)GCT cell lines including those resistant to cisplatin. In silico results were validated in 261 patient samples and differential expression of HDACs was also observed across cell lines. Belinostat and panobinostat reduced cell viability in both cisplatin-sensitive cells (NCCIT-P, 2102Ep-P, and NT2-P) and, importantly, also in matched cisplatin-resistant subclones (NCCIT-R, 2102Ep-R, and NT2-R), with IC50s in the low nanomolar range for all cell lines. Treatment of NCCIT-R with both drugs increased acetylation, induced cell cycle arrest, reduced proliferation, decreased Ki67 index, and increased p21, while increasing cell death by apoptosis, with upregulation of cleaved caspase 3. These findings support the effectiveness of HDACis for treating TGCT patients in general, including those developing cisplatin resistance. Future studies should explore them as single or combination agents.
PubMed: 33050470
DOI: 10.3390/cancers12102903 -
Dermatology and Therapy Jun 2021Atopic dermatitis (AD) is a highly prevalent chronic inflammatory skin disease that is characterized by intense pruritus, seriously affecting patients' quality of life....
Atopic dermatitis (AD) is a highly prevalent chronic inflammatory skin disease that is characterized by intense pruritus, seriously affecting patients' quality of life. Its pathophysiology, which involves both the adaptive and innate immune responses as well as skin barrier defects, is still poorly understood. We recently identified a microRNA, miR-335, as a key driver of keratinocyte differentiation and cornification, which is essential for the establishment of a healthy skin barrier. However, expression of miR-335 is lost in AD, leading to barrier defect. We further demonstrated how belinostat, a histone deacetylase inhibitor, can effectively restore miR-335 and resolve the barrier defect in a dry skin model. Here, in this commentary, we highlight the role of belinostat in the treatment of AD and discuss the need for more research into crosstalk between epigenetic and non-coding RNA-based regulation, as well as possible therapeutic strategies targeting the epigenome.
PubMed: 33852133
DOI: 10.1007/s13555-021-00527-7 -
Leukemia & Lymphoma May 2021We report the results of a phase 1 dose-escalation study of belinostat and bortezomib in adult patients with acute leukemia or MDS or CML with blast crisis. Thirty-eight...
We report the results of a phase 1 dose-escalation study of belinostat and bortezomib in adult patients with acute leukemia or MDS or CML with blast crisis. Thirty-eight patients received IV belinostat days 1-5 and 8-12 with IV bortezomib days 1, 4, 8, and 11 every 21 days. QTc prolongation was the only identified DLT. The RP2Ds were 1.3 mg/m bortezomib and 1000 mg/m belinostat. One patient with highly refractory rearranged biphenotypic AML with multiple karyotypic aberrations had a complete pathologic and karyotypic response. One patient with post-MPN AML remained on study with stable disease (SD) for 32 cycles. Whole-exome sequencing revealed no aberrations in the first patient and a hyper-mutator genotype in the second. Eighteen patients had a best response of SD. We conclude that this treatment strategy is feasible but has limited activity in this population. Nevertheless, the factors that predict exceptional responses to this strategy warrant further investigation.
Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Humans; Hydroxamic Acids; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Sulfonamides; Treatment Outcome
PubMed: 33356689
DOI: 10.1080/10428194.2020.1861270 -
Cancers Mar 2021Multi-gene assays often include and, in certain instances, may report associated toxicity risks for irinotecan, belinostat, pazopanib, and nilotinib. However, guidance... (Review)
Review
Multi-gene assays often include and, in certain instances, may report associated toxicity risks for irinotecan, belinostat, pazopanib, and nilotinib. However, guidance for incorporating results into therapeutic decision-making is mostly lacking for these anticancer drugs. We summarized meta-analyses, genome-wide association studies, clinical trials, drug labels, and guidelines relating to the impact of polymorphisms on irinotecan, belinostat, pazopanib, or nilotinib toxicities. For irinotecan, was significantly associated with neutropenia and diarrhea, particularly with doses ≥ 180 mg/m, supporting the use of to guide irinotecan prescribing. The drug label for belinostat recommends a reduced starting dose of 750 mg/m for homozygotes, though published studies supporting this recommendation are sparse. There was a correlation between polymorphisms and pazopanib-induced hepatotoxicity, though further studies are needed to elucidate the role of -guided pazopanib dose adjustments. Limited studies have investigated the association between polymorphisms and nilotinib-induced hepatotoxicity, with data currently insufficient for -guided nilotinib dose adjustments.
PubMed: 33805415
DOI: 10.3390/cancers13071566 -
Tomography (Ann Arbor, Mich.) Mar 2022Glioblastoma (GBM) is highly aggressive and has a poor prognosis. Belinostat is a histone deacetylase inhibitor with blood-brain barrier permeability, anti-GBM activity,...
Final Report on Clinical Outcomes and Tumor Recurrence Patterns of a Pilot Study Assessing Efficacy of Belinostat (PXD-101) with Chemoradiation for Newly Diagnosed Glioblastoma.
Glioblastoma (GBM) is highly aggressive and has a poor prognosis. Belinostat is a histone deacetylase inhibitor with blood-brain barrier permeability, anti-GBM activity, and the potential to enhance chemoradiation. The purpose of this clinical trial was to assess the efficacy of combining belinostat with standard-of-care therapy. Thirteen patients were enrolled in each of control and belinostat cohorts. The belinostat cohort was given a belinostat regimen (500-750 mg/m 1×/day × 5 days) every three weeks (weeks 0, 3, and 6 of RT). All patients received temozolomide and radiation therapy (RT). RT margins of 5-10 mm were added to generate clinical tumor volumes and 3 mm added to create planning target volumes. Median overall survival (OS) was 15.8 months for the control cohort and 18.5 months for the belinostat cohort ( = 0.53). The recurrence volumes (rGTVs) for the control cohort occurred in areas that received higher radiation doses than that in the belinostat cohort. For those belinostat patients who experienced out-of-field recurrence, tumors were detectable by spectroscopic MRI before RT. Recurrence analysis suggests better in-field control with belinostat. This study highlights the potential of belinostat as a synergistic therapeutic agent for GBM. It may be particularly beneficial to combine this radio-sensitizing effect with spectroscopic MRI-guided RT.
Topics: Glioblastoma; Humans; Hydroxamic Acids; Neoplasm Recurrence, Local; Pilot Projects; Sulfonamides
PubMed: 35314634
DOI: 10.3390/tomography8020057 -
Pharmaceuticals (Basel, Switzerland) Dec 2019ZL277 is a prodrug of belinostat with enhanced bioavailability and efficacy as a pan histone deacetylase (HDAC) inhibitor. In this study, we investigated the metabolism...
ZL277 is a prodrug of belinostat with enhanced bioavailability and efficacy as a pan histone deacetylase (HDAC) inhibitor. In this study, we investigated the metabolism and pharmacokinetics of ZL277 in liver S9 fractions, liver microsomes, liver cytosol, and in mice. Metabolic products were identified and quantified by a combination of liquid chromatography and tandem mass spectrometry. The in vitro metabolic profile of ZL277 includes ZL277-B(OH)-452, the major oxidative metabolite ZL277-OH-424, the active ingredient belinostat, belinostat amide, belinostat acid, and methylated belinostat in liver S9 fractions. Both ZL277-OH-424 and belinostat underwent further glucuronidation in liver microsome, whereas only ZL277-OH-424, but not belinostat, underwent some level of sulfation in rat liver cytosols. These metabolites were examined in plasma and in a breast tumor model in vivo. They were also examined in urine and feces from mice treated with ZL277. The pharmacokinetic study of ZL277 showed the parameters of active drug belinostat with a half-life (t) of 10.7 h, an area under curve value (AUC) of 1506.9 ng/mL*h, and a maximum plasma concentration (C) of 172 ng/mL, reached 3 h after a single dose of 10 mg/kg. The hydrolysis product of the prodrug, ZL277-B(OH)-452 showed an AUC of 8306 ng/mL*h and C of 931 ng/mL 3 h after drug administration.
PubMed: 31817969
DOI: 10.3390/ph12040180 -
World Journal of Hepatology Nov 2021Liver cancer is the sixth most commonly occurring cancer and costs millions of lives per year. The diagnosis of hepatocellular carcinoma (HCC) has relied on scanning... (Review)
Review
Liver cancer is the sixth most commonly occurring cancer and costs millions of lives per year. The diagnosis of hepatocellular carcinoma (HCC) has relied on scanning techniques and serum-based markers such as α-fetoprotein. These measures have limitations due to their detection limits and asymptomatic conditions during the early stages, resulting in late-stage cancer diagnosis where targeted chemotherapy or systemic treatment with sorafenib is offered. However, the aid of conventional therapy for patients in the advanced stage of HCC has limited outcomes. Thus, it is essential to seek a new treatment strategy and improve the diagnostic techniques to manage the disease. Researchers have used the omics profile of HCC patients for sub-classification of tissues into different groups, which has helped us with prognosis. Despite these efforts, a promising target for treatment has not been identified. The hurdle in this situation is genetic and epigenetic variations in the tumor, leading to disparities in response to treatment. Understanding reversible epigenetic changes along with clinical traits help to define new markers for patient categorization and design personalized therapy. Many clinical trials of inhibitors of epigenetic modifiers (also known as epi-drugs) are in progress. Epi-drugs like azacytidine or belinostat are already approved for other cancer treatments. Furthermore, epigenetic changes have also been observed in drug-resistant HCC tumors. In such cases, combinatorial treatment of epi-drugs with systemic therapy or trans-arterial chemoembolization might re-sensitize resistant cells.
PubMed: 34904030
DOI: 10.4254/wjh.v13.i11.1568 -
Frontiers in Cell and Developmental... 2020Pralatrexate (Folotyn; PLX) and belinostat (Beleodaq; BLS) are registered for the treatment of patients with peripheral T-cell lymphoma (PTCL) and are being considered...
Pralatrexate (Folotyn; PLX) and belinostat (Beleodaq; BLS) are registered for the treatment of patients with peripheral T-cell lymphoma (PTCL) and are being considered for other lymphomas. In this study we investigated whether BLS had the ability to potentiate the cytotoxicity of PLX. A panel of lymphoma cell lines was used for the combination studies: the B-cell SUDHL-4, SUDHL-5, HT, Jeko-1 and T-cell Karpas-299 and Hut-78. Uptake of PLX was mediated by the reduced folate carrier (RFC). PLX showed a 6-fold better RFC substrate affinity compared to methotrexate, and 2-fold better than levoleucovorin (l-LV). Sensitivity expressed as the concentration that resulted in 50% growth inhibition (IC50) after 72 hr exposure to PLX varied from 2.8 to 20 nM and for BLS from 72 to 233 nM, independent of the background of the cell lines. The interaction between BLS and PLX was studied using the median-drug effect analysis. At a fixed molar ratio between the drugs based on the IC50 concentration the average combination index (CI) for all cell lines showed additivity (CI: around 1.0). In three selected cell lines (SUDHL-4, SUDHL-5, and HT) sequential exposure (24 h pretreatment with BLS, followed by 48 h to PLX + BLS), did not improve interaction (CI: 0.9-1.4). As an alternative approach a non-fixed ratio was used by exposing SUDHL-4, SUDHL-5, and HT cells to IC25 concentrations of either BLS or PLX in combination with the other drug. Exposure to IC25 of PLX did not decrease the IC50 for BLS (CI from 0.6-1.2), but exposure to IC25 of BLS markedly increased PLX sensitivity (low CIs from 0.40 to 0.66). Mechanistic studies focused on induction of apoptosis, and showed cleavage of predominantly caspase-9 in HT and SUDHL-4 cells for both drugs at their IC50s, being similar in the combination setting. Moreover, at these concentrations, the drugs were shown to confer an S-phase arrest. In conclusion, the combination of PLX and BLS showed additivity in various lymphoma cell lines, with a schedule-dependent synergism in B-cell lymphoma. Based on these data, proficient inhibition of HDAC activity by BLS holds promise in sensitization of tumor cells to PLX.
PubMed: 33163492
DOI: 10.3389/fcell.2020.577215