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Pharmaceutics Jun 2023The indole heterocycle represents one of the most important scaffolds in medicinal chemistry and is shared among a number of drugs clinically used in different... (Review)
Review
The indole heterocycle represents one of the most important scaffolds in medicinal chemistry and is shared among a number of drugs clinically used in different therapeutic areas. Due to its varied biological activities, high unique chemical properties and significant pharmacological behaviors, indole derivatives have drawn considerable interest in the last decade as antitumor agents active against different types of cancers. The research of novel antiproliferative drugs endowed with enhanced efficacy and reduced toxicity led to the approval by U.S. Food and Drug Administration of the indole-based anticancer agents Sunitinib, Nintedanib, Osimertinib, Panobinostat, Alectinib and Anlotinib. Additionally, new drug delivery systems have been developed to protect the active principle from degradation and to direct the drug to the specific site for clinical use, thus reducing its toxicity. In the present work is an updated review of the recently approved indole-based anti-cancer agents and the nanotechnology systems developed for their delivery.
PubMed: 37514002
DOI: 10.3390/pharmaceutics15071815 -
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 -
Current Oncology Reports Feb 2020H3K27M is a frequent histone mutation within diffuse midline gliomas and is associated with a dismal prognosis, so much so that the 2016 CNS WHO classification system... (Review)
Review
PURPOSE OF REVIEW
H3K27M is a frequent histone mutation within diffuse midline gliomas and is associated with a dismal prognosis, so much so that the 2016 CNS WHO classification system created a specific category of "Diffuse Midline Glioma, H3K27M-mutant". Here we outline the latest pre-clinical data and ongoing current clinical trials that target H3K27M, as well as explore diagnosis and treatment monitoring by serial liquid biopsy.
RECENT FINDINGS
Multiple epigenetic compounds have demonstrated efficacy and on-target effects in pre-clinical models. The imipridone ONC201 and the IDO1 inhibitor indoximod have demonstrated early clinical activity against H3K27M-mutant gliomas. Liquid biopsy of cerebrospinal fluid has shown promise for clinical use in H3K27M-mutant tumors for diagnosis and monitoring treatment response. While H3K27M has elicited a widespread platform of pre-clinical therapies with promise, much progress still needs to be made to improve outcomes for diffuse midline glioma patients. We present current treatment and monitoring techniques as well as novel approaches in identifying and targeting H3K27M-mutant gliomas.
Topics: Antineoplastic Agents; Brain Neoplasms; Cerebrospinal Fluid; Clinical Trials as Topic; Glioma; Histone Deacetylase Inhibitors; Humans; Immunotherapy, Adoptive; Jumonji Domain-Containing Histone Demethylases; Liquid Biopsy; Mutation; Prognosis; Spinal Cord Neoplasms
PubMed: 32030483
DOI: 10.1007/s11912-020-0877-0 -
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 -
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 -
ImmunoTargets and Therapy 2021Whereas the treatment of MM was dependent solely on alkylating agents and corticosteroids during the prior three decades, the landscape of therapeutic measures to treat... (Review)
Review
Whereas the treatment of MM was dependent solely on alkylating agents and corticosteroids during the prior three decades, the landscape of therapeutic measures to treat the disease began to expand enormously early in the current century. The introduction of new classes of small-molecule drugs, such as proteasome blockers (bortezomib and carfilzomib), immunomodulators (lenalidomide and pomalidomide), nuclear export inhibitors (selinexor), and histone deacetylase blockers (panobinostat), as well as the application of autologous stem cell transplantation (ASCT), resulted in a seismic shift in how the disease is treated. The picture changed dramatically once again starting with the 2015 FDA approval of two monoclonal antibodies (mAbs) - the anti-CD38 daratumumab and the anti-SLAMF7 elotuzumab. Daratumumab, in particular, has had a great impact on MM therapy and today is often included in various regimens to treat the disease, both in newly diagnosed cases and in the relapse/refractory setting. Recently, other immunotherapies have been added to the arsenal of drugs available to fight this malignancy. These include isatuximab (also anti-CD38) and, in the past year, the antibody-drug conjugate (ADC) belantamab mafodotin and the chimeric antigen receptor (CAR) T-cell product idecabtagene vicleucel (ide-cel). While the accumulated benefits of these newer agents have resulted in a doubling of the disease's five-year survival rate to more than 5 years and improved quality of life, the disease remains incurable. Almost without exception patients experience relapse and/or become refractory to the drugs used, making the search for innovative therapies all the more essential. This review covers the current scope of anti-myeloma immunotherapeutic agents, both those in clinical use and on the horizon, including naked mAbs, ADCs, bi- and multi-targeted mAbs, and CAR T-cells. Emphasis is placed on the benefits of each along with the challenges that need to be overcome if MM is to be considered curable in the future.
PubMed: 34527606
DOI: 10.2147/ITT.S306103 -
Journal of Experimental & Clinical... Nov 2022Medulloblastoma (MB) patients with MYC oncogene amplification or overexpression exhibit extremely poor clinical outcomes and respond poorly to current therapies....
BACKGROUND
Medulloblastoma (MB) patients with MYC oncogene amplification or overexpression exhibit extremely poor clinical outcomes and respond poorly to current therapies. Epigenetic deregulation is very common in MYC-driven MB. The bromodomain extra-terminal (BET) proteins and histone deacetylases (HDACs) are epigenetic regulators of MYC transcription and its associated tumorigenic programs. This study aimed to investigate the therapeutic potential of inhibiting the BET proteins and HDACs together in MB.
METHODS
Using clinically relevant BET inhibitors (JQ1 or OTX015) and a pan-HDAC inhibitor (panobinostat), we evaluated the effects of combined inhibition on cell growth/survival in MYC-amplified MB cell lines and xenografts and examined underlying molecular mechanism(s).
RESULTS
Co-treatment of JQ1 or OTX015 with panobinostat synergistically suppressed growth/survival of MYC-amplified MB cells by inducing G2 cell cycle arrest and apoptosis. Mechanistic investigation using RNA-seq revealed that co-treatment of JQ1 with panobinostat synergistically modulated global gene expression including MYC/HDAC targets. SYK and MSI1 oncogenes were among the top 50 genes synergistically downregulated by JQ1 and panobinostat. RT-PCR and western blot analyses confirmed that JQ1 and panobinostat synergistically inhibited the mRNA and protein expression of MSI1/SYK along with MYC expression. Reduced SYK/MSI expression after BET (specifically, BRD4) gene-knockdown further confirmed the epigenetic regulation of SYK and MSI1 genes. In addition, the combination of OTX015 and panobinostat significantly inhibited tumor growth in MYC-amplified MB xenografted mice by downregulating expression of MYC, compared to single-agent therapy.
CONCLUSIONS
Together, our findings demonstrated that dual-inhibition of BET and HDAC proteins of the epigenetic pathway can be a novel therapeutic approach against MYC-driven MB.
Topics: Humans; Mice; Animals; Medulloblastoma; Histone Deacetylases; Nuclear Proteins; Panobinostat; Azepines; Epigenesis, Genetic; Cell Cycle Proteins; Cell Line, Tumor; Transcription Factors; Triazoles; Apoptosis; Cell Proliferation; Cerebellar Neoplasms; Proto-Oncogene Proteins c-myc
PubMed: 36357906
DOI: 10.1186/s13046-022-02530-y -
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