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Pharmacogenomics Nov 2016The histone deacetylase inhibitor valproic acid (VPA) has been used for many decades in neurology and psychiatry. The more recent introduction of the histone deacetylase... (Review)
Review
The histone deacetylase inhibitor valproic acid (VPA) has been used for many decades in neurology and psychiatry. The more recent introduction of the histone deacetylase inhibitors (HDIs) belinostat, romidepsin and vorinostat for treatment of hematological malignancies indicates the increasing popularity of these agents. Belinostat, romidepsin and vorinostat are metabolized or transported by polymorphic enzymes or drug transporters. Thus, genotype-directed dosing could improve pharmacotherapy by reducing the risk of toxicities or preventing suboptimal treatment. This review provides an overview of clinical studies on the effects of polymorphisms on the pharmacokinetics, efficacy or toxicities of HDIs including belinostat, romidepsin, vorinostat, panobinostat, VPA and a number of novel compounds currently being tested in Phase I and II trials. Although pharmacogenomic studies for HDIs are scarce, available data indicate that therapy with belinostat (UGT1A1), romidepsin (ABCB1), vorinostat (UGT2B17) or VPA (UGT1A6) could be optimized by upfront genotyping.
Topics: Depsipeptides; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Indoles; Panobinostat; Pharmacogenetics; Sulfonamides; Valproic Acid; Vorinostat
PubMed: 27767376
DOI: 10.2217/pgs-2016-0113 -
Molecular Oncology Sep 2023In previous studies, we demonstrated that panobinostat, a histone deacetylase inhibitor, and bortezomib, a proteasomal inhibitor, displayed synergistic therapeutic...
In previous studies, we demonstrated that panobinostat, a histone deacetylase inhibitor, and bortezomib, a proteasomal inhibitor, displayed synergistic therapeutic activity against pediatric and adult high-grade gliomas. Despite the remarkable initial response to this combination, resistance emerged. Here, in this study, we aimed to investigate the molecular mechanisms underlying the anticancer effects of panobinostat and marizomib, a brain-penetrant proteasomal inhibitor, and the potential for exploitable vulnerabilities associated with acquired resistance. RNA sequencing followed by gene set enrichment analysis (GSEA) was employed to compare the molecular signatures enriched in resistant compared with drug-naïve cells. The levels of adenosine 5'-triphosphate (ATP), nicotinamide adenine dinucleotide (NAD) content, hexokinase activity, and tricarboxylic acid (TCA) cycle metabolites required for oxidative phosphorylation to meet their bioenergetic needs were analyzed. Here, we report that panobinostat and marizomib significantly depleted ATP and NAD content, increased mitochondrial permeability and reactive oxygen species generation, and promoted apoptosis in pediatric and adult glioma cell lines at initial treatment. However, resistant cells exhibited increased levels of TCA cycle metabolites, which required for oxidative phosphorylation to meet their bioenergetic needs. Therefore, we targeted glycolysis and the electron transport chain (ETC) with small molecule inhibitors, which displayed substantial efficacy, suggesting that resistant cell survival is dependent on glycolytic and ETC complexes. To verify these observations in vivo, lonidamine, an inhibitor of glycolysis and mitochondrial function, was chosen. We produced two diffuse intrinsic pontine glioma (DIPG) models, and lonidamine treatment significantly increased median survival in both models, with particularly dramatic effects in panobinostat- and marizomib-resistant cells. These data provide new insights into mechanisms of treatment resistance in gliomas.
Topics: Humans; Adult; Child; Panobinostat; NAD; Glioma; Proteasome Inhibitors; Mitochondria; Cell Line, Tumor
PubMed: 37014128
DOI: 10.1002/1878-0261.13427 -
Leukemia Jun 2023In AML with NPM1 mutation causing cytoplasmic dislocation of NPM1, treatments with Menin inhibitor (MI) and standard AML chemotherapy yield complete remissions. However,...
In AML with NPM1 mutation causing cytoplasmic dislocation of NPM1, treatments with Menin inhibitor (MI) and standard AML chemotherapy yield complete remissions. However, the causal and mechanistic linkage of mtNPM1 to the efficacy of these agents has not been definitively established. Utilizing CRISPR-Cas9 editing to knockout (KO) or knock-in a copy of mtNPM1 in AML cells, present studies demonstrate that KO of mtNPM1 from AML cells abrogates sensitivity to MI, selinexor (exportin-1 inhibitor), and cytarabine. Conversely, the knock-in of a copy of mtNPM1 markedly sensitized AML cells to treatment with MI or cytarabine. Following AML therapy, most elderly patients with AML with mtNPM1 and co-mutations in FLT3 suffer AML relapse with poor outcomes, creating a need for novel effective therapies. Utilizing the RNA-Seq signature of CRISPR-edited AML cells with mtNPM1 KO, we interrogated the LINCS1000-CMap data set and found several pan-HDAC inhibitors and a WEE1 tyrosine kinase inhibitor among the top expression mimickers (EMs). Additionally, treatment with adavosertib (WEE1 inhibitor) or panobinostat (pan-HDAC inhibitor) exhibited synergistic in vitro lethal activity with MI against AML cells with mtNPM1. Treatment with adavosertib or panobinostat also reduced AML burden and improved survival in AML xenograft models sensitive or resistant to MI.
Topics: Humans; Aged; Nuclear Proteins; Nucleophosmin; Panobinostat; Neoplasm Recurrence, Local; Mutation; Cytarabine; Leukemia, Myeloid, Acute; fms-Like Tyrosine Kinase 3
PubMed: 36977823
DOI: 10.1038/s41375-023-01882-4 -
Scientific Reports Aug 2023Low-grade and secondary high-grade gliomas frequently contain mutations in the IDH1 or IDH2 metabolic enzymes that are hypothesized to drive tumorigenesis by inhibiting...
Low-grade and secondary high-grade gliomas frequently contain mutations in the IDH1 or IDH2 metabolic enzymes that are hypothesized to drive tumorigenesis by inhibiting many of the chromatin-regulating enzymes that regulate DNA structure. Histone deacetylase inhibitors are promising anti-cancer agents and have already been used in clinical trials. However, a clear understanding of their mechanism or gene targets is lacking. In this study, the authors genetically dissect patient-derived IDH1 mutant cultures to determine which HDAC enzymes drive growth in IDH1 mutant gliomas. A panel of patient-derived gliomasphere cell lines (2 IDH1 mutant lines, 3 IDH1 wildtype lines) were subjected to a drug-screen of epigenetic modifying drugs from different epigenetic classes. The effect of LBH (panobinostat) on gene expression and chromatin structure was tested on patient-derived IDH1 mutant lines. The role of each of the highly expressed HDAC enzymes was molecularly dissected using lentiviral RNA interference knock-down vectors and a patient-derived IDH1 mutant in vitro model of glioblastoma (HK252). These results were then confirmed in an in vivo xenotransplant model (BT-142). The IDH1 mutation leads to gene down-regulation, DNA hypermethylation, increased DNA accessibility and H3K27 hypo-acetylation in two distinct IDH1 mutant over-expression models. The drug screen identified histone deacetylase inhibitors (HDACi) and panobinostat (LBH) more specifically as the most selective compounds to inhibit growth in IDH1 mutant glioma lines. Of the eleven annotated HDAC enzymes (HDAC1-11) only six are expressed in IDH1 mutant glioma tissue samples and patient-derived gliomasphere lines (HDAC1-4, HDAC6, and HDAC9). Lentiviral knock-down experiments revealed that HDAC1 and HDAC6 are the most consistently essential for growth both in vitro and in vivo and target very different gene modules. Knock-down of HDAC1 or HDAC6 in vivo led to a more circumscribed less invasive tumor. The gene dysregulation induced by the IDH1 mutation is wide-spread and only partially reversible by direct IDH1 inhibition. This study identifies HDAC1 and HDAC6 as important and drug-targetable enzymes that are necessary for growth and invasiveness in IDH1 mutant gliomas.
Topics: Humans; Panobinostat; Histone Deacetylase Inhibitors; Glioma; Antineoplastic Agents; Chromatin; Isocitrate Dehydrogenase; Mutation; Brain Neoplasms; Histone Deacetylase 1; Histone Deacetylase 6
PubMed: 37528157
DOI: 10.1038/s41598-023-33889-3 -
Expert Review of Hematology Mar 2017A significant unmet need exists in patients with relapsed or refractory multiple myeloma (MM), which remains an incurable disease despite recent advances in the field.... (Review)
Review
A significant unmet need exists in patients with relapsed or refractory multiple myeloma (MM), which remains an incurable disease despite recent advances in the field. One such development was the use of deacetylase inhibitors (DACi), which exert unique antimyeloma effects through targeting of epigenetic and protein metabolism pathways. The pan-DACi panobinostat was recently approved in combination with bortezomib and dexamethasone for use in patients with relapsed or relapsed and refractory MM. Results of a phase 3 trial showed that the panobinostat-containing regimen improved the overall response rate and progression-free survival. Panobinostat-associated adverse events included thrombocytopenia, diarrhea, fatigue, and peripheral neuropathy. Research into how to maintain the benefits of DACi while improving tolerability is ongoing. Areas covered: This review focuses on the efficacy and safety of panobinostat and panobinostat-based combinations for MM. Early data from clinical trials investigating the HDAC6 inhibitor ricolinostat are also discussed. Expert commentary: DACi are a unique and effective new class of agents for the treatment of MM, with panobinostat being the first to have clinically meaningful benefit for patients with relapsed or refractory MM. Optimization of dose and schedule, novel combination strategies, and introduction of selective DACi may improve the risk-benefit profile of DACi-based regimens.
Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Clinical Trials as Topic; Dexamethasone; Drug Discovery; Drug Resistance, Neoplasm; Epigenesis, Genetic; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Indoles; Molecular Targeted Therapy; Multiple Myeloma; Panobinostat; Recurrence
PubMed: 28076695
DOI: 10.1080/17474086.2017.1280388 -
Prescrire International Nov 2016Patients with relapsed or refractory multiple myeloma who have received several lines of therapy have no satisfactory treatment options. High-dose corticosteroid therapy... (Review)
Review
Patients with relapsed or refractory multiple myeloma who have received several lines of therapy have no satisfactory treatment options. High-dose corticosteroid therapy or a combination of low-dose dexamethasone and pomaildomide may be proposed. Panobinostat is the first histone deacetylase (HDAC) inhibitor to be authorised in the European Union for use in this indication. A randomised, double-blind, placebo-controlled trial evaluated panobinostat in 768 patients with relapsed or refractory multiple myeloma who were also receiving bortezomib + dexamethasone. Panobinostat did not prolong survival. The median time to myeloma progression, relapse, or death was prolonged by about 3 months with the panobinostat-containing combination, and by a median of about 8 months in the subgroup of patients who had received at least two lines of chemotherapy including bortezomib and an "immunomodulatory" drug. There was no statistically significant increase in survival, however. In this trial, adverse events led one in six patients to discontinue panobinostat and resulted in numerous hospital admissions. The proportion of patients who died from causes unrelated to myeloma was 6.8% in the panobinostat group versus 3.2% In the placebo group. The toxicity of panobinostat affects most vital functions, resulting in a risk of infections as well as haematological, gastrointestinal, cardiac, renal, hepatic and thyroid disorders. These adverse effects are often severe and sometimes fatal. Panobinostat is subject to pharmacokinetic interactions via cytochrome P450 enzymes and P-glycoproteln, and also to pharmacodynamic Interactions. Panobinostat was teratogenic in animal studies. In practice, even when several previous lines of treatment have failed, panobinostatis more toxic than useful In patients with myeloma. It should therefore not be used.
Topics: Antineoplastic Agents; Arrhythmias, Cardiac; Chemical and Drug Induced Liver Injury; Cost-Benefit Analysis; Diarrhea; Drug Interactions; Gastrointestinal Diseases; Hemorrhage; Humans; Hypothyroidism; Infections; Mortality; Multiple Myeloma; Myocardial Ischemia; Neutropenia; Panobinostat; Progression-Free Survival; Renal Insufficiency; Survival Rate; Thrombocytopenia
PubMed: 30715819
DOI: No ID Found -
Aging Oct 2021
Topics: Child; Glioma; Histone Deacetylase Inhibitors; Histones; Humans; Mutation; Nerve Tissue Proteins; Panobinostat; Phosphoproteins; Proteome; Proteomics; Signal Transduction; Sodium-Hydrogen Exchangers; Tumor Cells, Cultured
PubMed: 34705668
DOI: 10.18632/aging.203659 -
Future Oncology (London, England) Mar 2017Multiple myeloma (MM) is the second most common blood cancer following non-Hodgkin's lymphoma. While the treatments for MM have improved over the past decade, for the... (Review)
Review
Multiple myeloma (MM) is the second most common blood cancer following non-Hodgkin's lymphoma. While the treatments for MM have improved over the past decade, for the most part, it remains an incurable disease. For this reason newer therapeutic agents are needed to combat this malignancy. Panobinostat is a pan-deacetylase inhibitor that impedes protein destruction by disturbing the enzymatic activity of deacetylases. It was US FDA approved in February 2015 for the management of relapsed/refractory MM in combination with bortezomib and dexamethasone. Several trials are ongoing, exploring the utility of panobinostat in various other settings for the management of MM. This review will detail the biology, clinical efficacy and potential future applications of panobinostat in the treatment of MM.
Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Disease Management; Drug Evaluation, Preclinical; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Hydroxamic Acids; Indoles; Multiple Myeloma; Panobinostat; Treatment Outcome
PubMed: 27776419
DOI: 10.2217/fon-2016-0329 -
Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML.Cancer Discovery Jun 2022Pharmacologic inhibition of epigenetic enzymes can have therapeutic benefit against hematologic malignancies. In addition to affecting tumor cell growth and...
UNLABELLED
Pharmacologic inhibition of epigenetic enzymes can have therapeutic benefit against hematologic malignancies. In addition to affecting tumor cell growth and proliferation, these epigenetic agents may induce antitumor immunity. Here, we discovered a novel immunoregulatory mechanism through inhibition of histone deacetylases (HDAC). In models of acute myeloid leukemia (AML), leukemia cell differentiation and therapeutic benefit mediated by the HDAC inhibitor (HDACi) panobinostat required activation of the type I interferon (IFN) pathway. Plasmacytoid dendritic cells (pDC) produced type I IFN after panobinostat treatment, through transcriptional activation of IFN genes concomitant with increased H3K27 acetylation at these loci. Depletion of pDCs abrogated panobinostat-mediated induction of type I IFN signaling in leukemia cells and impaired therapeutic efficacy, whereas combined treatment with panobinostat and IFNα improved outcomes in preclinical models. These discoveries offer a new therapeutic approach for AML and demonstrate that epigenetic rewiring of pDCs enhances antitumor immunity, opening the possibility of exploiting this approach for immunotherapies.
SIGNIFICANCE
We demonstrate that HDACis induce terminal differentiation of AML through epigenetic remodeling of pDCs, resulting in production of type I IFN that is important for the therapeutic effects of HDACis. The study demonstrates the important functional interplay between the immune system and leukemias in response to HDAC inhibition. This article is highlighted in the In This Issue feature, p. 1397.
Topics: Cell Differentiation; Dendritic Cells; Epigenesis, Genetic; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Leukemia, Myeloid, Acute; Panobinostat
PubMed: 35311997
DOI: 10.1158/2159-8290.CD-20-1145 -
European Journal of Medicinal Chemistry Sep 2023Multiple myeloma (MM) is a hematologic neoplasm of plasma cells that is currently deemed incurable. Despite the introduction of novel immunomodulators and proteasome... (Review)
Review
Multiple myeloma (MM) is a hematologic neoplasm of plasma cells that is currently deemed incurable. Despite the introduction of novel immunomodulators and proteasome inhibitors, MM remains a challenging disease with high rates of relapse and refractoriness. The management of refractory and relapsed MM patients remains a formidable task, primarily due to the emergence of multiple drug resistance. Consequently, there is an urgent need for novel therapeutic agents to address this clinical challenge. In recent years, a significant amount of research has been dedicated to the discovery of novel therapeutic agents for the treatment of MM. The clinical utilization of proteasome inhibitor carfilzomib and immunomodulator pomalidomide has been successively introduced. As basic research continues to advance, novel therapeutic agents, including panobinostat, a histone deacetylase inhibitor, and selinexor, a nuclear export inhibitor, have progressed to the clinical trial and application phase. This review aims to furnish a comprehensive survey of the clinical applications and synthetic pathways of select drugs, with the intention of imparting valuable insights for future drug research and development geared towards MM.
Topics: Humans; Multiple Myeloma; Neoplasm Recurrence, Local; Panobinostat; Histone Deacetylase Inhibitors; Proteasome Inhibitors; Immunologic Factors; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37210838
DOI: 10.1016/j.ejmech.2023.115492