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Neuro-oncology Dec 2023Diffuse intrinsic pontine glioma (DIPG) is a lethal childhood cancer with median survival of less than 1 year. Panobinostat is an oral multihistone deacetylase inhibitor...
BACKGROUND
Diffuse intrinsic pontine glioma (DIPG) is a lethal childhood cancer with median survival of less than 1 year. Panobinostat is an oral multihistone deacetylase inhibitor with preclinical activity in DIPG models. Study objectives were to determine safety, tolerability, maximum tolerated dose (MTD), toxicity profile, and pharmacokinetics of panobinostat in children with DIPG.
PATIENTS AND METHODS
In stratum 1, panobinostat was administered 3 days per week for 3 weeks on, 1 week off to children with progressive DIPG, with dose escalation following a two-stage continual reassessment method. After this MTD was determined, the study was amended to evaluate the MTD in children with nonprogressive DIPG/Diffuse midline glioma (DMG) (stratum 2) on an alternate schedule, 3 days a week every other week in an effort to escalate the dose.
RESULTS
For stratum 1, 19 subjects enrolled with 17/19 evaluable for dose-finding. The MTD was 10 mg/m2/dose. Dose-limiting toxicities included thrombocytopenia and neutropenia. Posterior reversible encephalopathy syndrome was reported in 1 patient. For stratum 2, 34 eligible subjects enrolled with 29/34 evaluable for dose finding. The MTD on this schedule was 22 mg/m2/dose. DLTs included thrombocytopenia, neutropenia, neutropenia with grade 4 thrombocytopenia, prolonged intolerable nausea, and increased ALT.
CONCLUSIONS
The MTD of panobinostat is 10 mg/m2/dose administered 3 times per week for 3 weeks on/1 week off in children with progressive DIPG/DMG and 22 mg/m2/dose administered 3 times per week for 1 week on/1 week off when administered in a similar population preprogression. The most common toxicity for both schedules was myelosuppression.
Topics: Child; Humans; Panobinostat; Diffuse Intrinsic Pontine Glioma; Posterior Leukoencephalopathy Syndrome; Glioma; Thrombocytopenia; Neutropenia; Brain Stem Neoplasms
PubMed: 37526549
DOI: 10.1093/neuonc/noad141 -
Acta Pharmacologica Sinica Apr 2024Osimertinib (Osi) is widely used as a first-line treatment for non-small cell lung cancer (NSCLC) with EGFR mutations. However, the majority of patients treated with Osi...
Osimertinib (Osi) is widely used as a first-line treatment for non-small cell lung cancer (NSCLC) with EGFR mutations. However, the majority of patients treated with Osi eventually relapse within a year. The mechanisms of Osi resistance remain largely unexplored, and efficient strategies to reverse the resistance are urgently needed. Here, we developed a lactoferrin-modified liposomal codelivery system for the combination therapy of Osi and panobinostat (Pan), an epigenetic regulator of histone acetylation. We demonstrated that the codelivery liposomes could efficiently repolarize tumor-associated macrophages (TAM) from the M2 to M1 phenotype and reverse the epithelial-mesenchymal transition (EMT)-associated drug resistance in the tumor cells, as well as suppress glycolysis, lactic acid production, and angiogenesis. Our results suggested that the combination therapy of Osi and Pan mediated by liposomal codelivery is a promising strategy for overcoming Osi resistance in NSCLC.
Topics: Humans; Acrylamides; Aniline Compounds; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Drug Resistance, Neoplasm; Epigenesis, Genetic; ErbB Receptors; Indoles; Liposomes; Lung Neoplasms; Mutation; Panobinostat; Protein Kinase Inhibitors; Pyrimidines; Tumor-Associated Macrophages
PubMed: 38114644
DOI: 10.1038/s41401-023-01205-4 -
Journal of Oncology 2020Panobinostat represents a potent oral nonselective pan-histone deacetylase inhibitor (HDAC) with activity in myeloma patients. It has been approved by the FDA and EMA in... (Review)
Review
Panobinostat represents a potent oral nonselective pan-histone deacetylase inhibitor (HDAC) with activity in myeloma patients. It has been approved by the FDA and EMA in combination with bortezomib and dexamethasone for the treatment of multiple myeloma, in patients who have received at least two prior regimens, including bortezomib and an immunomodulatory agent. In order to further explore its clinical potential, it is evaluated in different combinations in relapsed/refractory and newly diagnosed multiple myeloma. This review focuses on available data about panobinostat's pharmacology and its role in clinical practice. This review will reveal panobinostat's efficacy as antimyeloma treatment, describing drug evolution from preclinical experimental administration to administration in phase III trials, which established its role in current clinical practice. Based on the latest data, we will present its mechanism of action, its efficacy, and most important issues regarding its toxicity profile. We will further try to shed light on its role in current and future therapeutic landscape of myeloma patients. Panobinostat retains its role in therapy of multiple myeloma because of its manageable toxicity profile and its efficacy, mainly in heavily pretreated multiple myeloma patients. These characteristics make it valuable also for novel regimens in combination with second-generation proteasome inhibitors, IMiDs, and monoclonal antibodies. Results of ongoing trials are expected to shed light on drug introduction in different therapeutic combinations or even at an earlier level of disease course.
PubMed: 32411240
DOI: 10.1155/2020/7131802 -
Science Translational Medicine Aug 2022Crescentic glomerulonephritis is characterized by vascular necrosis and parietal epithelial cell hyperplasia in the space surrounding the glomerulus, resulting in the...
Crescentic glomerulonephritis is characterized by vascular necrosis and parietal epithelial cell hyperplasia in the space surrounding the glomerulus, resulting in the formation of crescents. Little is known about the molecular mechanisms driving this process. Inducing crescentic glomerulonephritis in two Pax2Cre reporter mouse models revealed that crescents derive from clonal expansion of single immature parietal epithelial cells. Preemptive and delayed histone deacetylase inhibition with panobinostat, a drug used to treat hematopoietic stem cell disorders, attenuated crescentic glomerulonephritis with recovery of kidney function in the two mouse models. Three-dimensional confocal microscopy and stimulated emission depletion superresolution imaging of mouse glomeruli showed that, in addition to exerting an anti-inflammatory and immunosuppressive effect, panobinostat induced differentiation of an immature hyperplastic parietal epithelial cell subset into podocytes, thereby restoring the glomerular filtration barrier. Single-cell RNA sequencing of human renal progenitor cells in vitro identified an immature stratifin-positive cell subset and revealed that expansion of this stratifin-expressing progenitor cell subset was associated with a poor outcome in human crescentic glomerulonephritis. Treatment of human parietal epithelial cells in vitro with panobinostat attenuated stratifin expression in renal progenitor cells, reduced their proliferation, and promoted their differentiation into podocytes. These results offer mechanistic insights into the formation of glomerular crescents and demonstrate that selective targeting of renal progenitor cells can attenuate crescent formation and the deterioration of kidney function in crescentic glomerulonephritis in mice.
Topics: Animals; Disease Models, Animal; Glomerulonephritis; Humans; Kidney; Mice; Panobinostat; Podocytes; Stem Cells
PubMed: 35947676
DOI: 10.1126/scitranslmed.abg3277 -
P & T : a Peer-reviewed Journal For... May 2015Filgrastim-sndz (Zarxio) to help prevent infections related to chemotherapy, dinutuximab (Unituxin) for high-risk pediatric neuroblastoma, and panobinostat (Farydak) for...
Filgrastim-sndz (Zarxio) to help prevent infections related to chemotherapy, dinutuximab (Unituxin) for high-risk pediatric neuroblastoma, and panobinostat (Farydak) for multiple myeloma.
PubMed: 25987820
DOI: No ID Found -
Current Pharmaceutical Design 2021Papillary Thyroid Cancer (PTC) is the most common type of endocrine malignancy. Although PTC has an excellent prognosis, the recurrent or metastatic disease could affect... (Review)
Review
BACKGROUND/AIM
Papillary Thyroid Cancer (PTC) is the most common type of endocrine malignancy. Although PTC has an excellent prognosis, the recurrent or metastatic disease could affect patients' survival. Recent studies show that Histone Deacetylase Inhibitors (HDACIs) might be promising anticancer agents against PTC. The aim of this review is to evaluate the role of HDACIs as an additional modality in PTC treatment and to depict the latest trends of current research on this field.
MATERIALS AND METHODS
This literature review was performed using the MEDLINE database. The search strategy included terms: "thyroid cancer", "papillary", "HDAC", "histone", and "deacetylase".
RESULTS
Agents, such as Suberoyl Anilide Hydroxamic Acid, Trichostatin A, Valproic Acid, Sodium butyrate, Panobinostat, Belinostat, Romidepsin, CUDC907 and N-Hydroxy-7-(2-naphthylthio)-Hepanomide have shown promising anti-cancer effects on PTC cell lines but fail to trigger a major response in clinical trials.
CONCLUSION
HDACIs have no significant effect as monotherapy against PTC, but further research needs to be conducted in order to investigate their potential effect when used as an additional modality.
Topics: Histone Deacetylase Inhibitors; Histones; Humans; Hydroxamic Acids; Panobinostat; Thyroid Cancer, Papillary; Thyroid Neoplasms
PubMed: 33308111
DOI: 10.2174/1381612826666201211112234 -
Expert Opinion on Investigational Drugs Sep 2016Therapeutic strategies in patients with acute myeloid leukemia (AML) have not changed significantly over the last decades. Appropriate strategies are ultimately driven... (Review)
Review
INTRODUCTION
Therapeutic strategies in patients with acute myeloid leukemia (AML) have not changed significantly over the last decades. Appropriate strategies are ultimately driven by the assessment of patients' fitness to define suitability for intensive induction chemotherapy, which produces high initial remission rates but, increased likelihood of relapse. Old/unfit AML patients still represent an urgent and unmet therapeutic need. Epigenetic deregulation represents a strategic characteristic of AML pathophysiology whereby aberrant gene transcription provides an advantage to leukemic cell survival. Efforts to re-establish impaired epigenetic regulation include hypomethylating agents and histone deacetylase inhibitors (HDACi).
AREAS COVERED
The review discusses the underlying mechanisms leading to disruption of lysine acetyltransferases (KAT or HAT)/deacetylase (KDAC or HDAC) balance and the rationale for using the HDACi panobinostat (LBH-589) in AML.
EXPERT OPINION
Although panobinostat has produced significant results in myeloma, its efficacy remains limited in AML. Panobinostat exerts pleiotropic activity and lack of specificity, which likely contributes to its inadequate safety in elderly AML patients. Phase I-II trials, utilizing panobinostat associated with well-known chemotherapeutic agents are ongoing and combinations with other druggable targets may likely be evaluated in future trials. The clinical use of this HDACi in AML the near future does not appearing promising.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; DNA Methylation; Drug Evaluation, Preclinical; Epigenesis, Genetic; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Indoles; Leukemia, Myeloid, Acute; Panobinostat; Treatment Outcome
PubMed: 27485472
DOI: 10.1080/13543784.2016.1216971 -
The Journal of Allergy and Clinical... Jun 2023X-linked MAGT1 deficiency with increased susceptibility to Epstein-Barr virus infection and N-linked glycosylation defect (XMEN) disease is a rare combined...
BACKGROUND
X-linked MAGT1 deficiency with increased susceptibility to Epstein-Barr virus infection and N-linked glycosylation defect (XMEN) disease is a rare combined immunodeficiency caused by loss-of-function mutations in the magnesium transporter 1 (MAGT1) gene. MAGT1 deficiency impairs magnesium transport and the N-linked glycosylation of a panel of proteins, which subsequently abolishes the expression of key immune receptors such as natural killer group 2, member D (aka NKG2D). These effects induce immune system abnormalities, chronic Epstein-Barr virus infection, and neoplasia. Recent research shows that MAGT1 and tumor candidate suppressor 3 (TUSC3) share high sequence and functional similarity.
OBJECTIVE
We sought to investigate the feasibility of activating TUSC3 expression to provide a potential therapeutic strategy for XMEN disease.
METHODS
The expression profiles of MAGT1 and TUSC3 were analyzed using multiple databases, real-time quantitative PCR, and Western blot. The effects of decitabine and panobinostat on the regulation of TUSC3 expression were explored in both MAGT1 knockout (KO)/patient-derived lymphocytes and MAGT1 KO hepatocytes.
RESULTS
Although TUSC3 is widely expressed, it is undetectable specifically in the immune system and liver, consistent with the main diseased tissues in patients with XMEN disease. CRISPR/Cas9-mediated KO of MAGT1 in the NKL cell line successfully mimicked the phenotypes of XMEN patient-derived lymphocytes, and exogenous expression of TUSC3 rescued the deficiencies in KO NKL cells. Using this in vitro model, we identified 2 epigenetic drugs, decitabine and panobinostat, by screening. Combination treatment using these 2 drugs significantly upregulated TUSC3 expression and rescued the immune and liver abnormalities.
CONCLUSIONS
Epigenetic activation of TUSC3 expression constitutes an effective therapeutic strategy for XMEN disease.
Topics: Humans; Magnesium; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Decitabine; Panobinostat; Epigenesis, Genetic
PubMed: 37086924
DOI: 10.1016/j.jaci.2023.04.003 -
Journal of Hepatology Apr 2024Patients with metastatic, treatment-refractory, and relapsed hepatoblastoma (HB) have survival rates of less than 50% due to limited treatment options. To develop new...
BACKGROUND & AIMS
Patients with metastatic, treatment-refractory, and relapsed hepatoblastoma (HB) have survival rates of less than 50% due to limited treatment options. To develop new therapeutic strategies for these patients, our laboratory has developed a preclinical testing pipeline. Given that histone deacetylase (HDAC) inhibition has been proposed for HB, we hypothesized that we could find an effective combination treatment strategy utilizing HDAC inhibition.
METHODS
RNA sequencing, microarray, NanoString, and immunohistochemistry data of patient HB samples were analyzed for HDAC class expression. Patient-derived spheroids (PDSp) were used to screen combination chemotherapy with an HDAC inhibitor, panobinostat. Patient-derived xenograft (PDX) mouse models were developed and treated with the combination therapy that showed the highest efficacy in the PDSp drug screen.
RESULTS
HDAC RNA and protein expression were elevated in HB tumors compared to normal livers. Panobinostat (IC of 0.013-0.059 μM) showed strong in vitro effects and was associated with lower cell viability than other HDAC inhibitors. PDSp demonstrated the highest level of cell death with combination treatment of vincristine/irinotecan/panobinostat (VIP). All four models responded to VIP therapy with a decrease in tumor size compared to placebo. After 6 weeks of treatment, two models demonstrated necrotic cell death, with lower Ki67 expression, decreased serum alpha fetoprotein and reduced tumor burden compared to paired VI- and placebo-treated groups.
CONCLUSIONS
Utilizing a preclinical HB pipeline, we demonstrate that panobinostat in combination with VI chemotherapy can induce an effective tumor response in models developed from patients with high-risk, relapsed, and treatment-refractory HB.
IMPACT AND IMPLICATIONS
Patients with treatment-refractory hepatoblastoma have limited treatment options with survival rates of less than 50%. Our manuscript demonstrates that combination therapy with vincristine, irinotecan, and panobinostat reduces the size of high-risk, relapsed, and treatment-refractory tumors. With this work we provide preclinical evidence to support utilizing this combination therapy as an arm in future clinical trials.
Topics: Humans; Mice; Animals; Panobinostat; Hepatoblastoma; Irinotecan; Vincristine; Neoplasm Recurrence, Local; Histone Deacetylase Inhibitors; Liver Neoplasms; Hydroxamic Acids
PubMed: 38242326
DOI: 10.1016/j.jhep.2024.01.003 -
Frontiers in Immunology 2022The viral transactivator Tax plays a key role in HTLV-1 reactivation and infection. Previous approaches focused on the histone deacetylase inhibitor (HDACi) Valproate...
The viral transactivator Tax plays a key role in HTLV-1 reactivation and infection. Previous approaches focused on the histone deacetylase inhibitor (HDACi) Valproate as a latency-reversing agent to boost Tax expression and expose infected cells to the host's immune response. However, following treatment with Valproate proviral load decreases in patients with HAM/TSP were only transient. Here, we hypothesize that other compounds, including more potent and selective HDACi, might prove superior to Valproate in manipulating Tax expression. Thus, a panel of HDACi (Vorinostat/SAHA/Zolinza, Panobinostat/LBH589/Farydak, Belinostat/PXD101/Beleodaq, Valproate, Entinostat/MS-275, Romidepsin/FK228/Istodax, and MC1568) was selected and tested for toxicity and potency in enhancing Tax expression. The impact of the compounds was evaluated in different model systems, including transiently transfected T-cells, chronically HTLV-1-infected T-cell lines, and freshly isolated PBMCs from HTLV-1 carriers . We identified the pan-HDACi Panobinostat and class I HDACi Romidepsin as particularly potent agents at raising Tax expression. qRT-PCR analysis revealed that these inhibitors considerably boost and Tax-target gene transcription. However, despite this significant increase in transcription and histone acetylation, protein levels of Tax were only moderately enhanced. In conclusion, these data demonstrate the ability of Panobinostat and Romidepsin to manipulate Tax expression and provide a foundation for further research into eliminating latently infected cells. These findings also contribute to a better understanding of conditions limiting transcription and translation of viral gene products.
Topics: Cell Line; Depsipeptides; Histone Deacetylase Inhibitors; Human T-lymphotropic virus 1; Humans; Panobinostat; T-Lymphocytes; Valproic Acid; Vorinostat
PubMed: 36052071
DOI: 10.3389/fimmu.2022.978800