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Scientific Reports Jun 2016During the past decades, many novel agents have improved response and survival of patients with multiple myeloma. Nevertheless, it remains challenging when they suffer... (Meta-Analysis)
Meta-Analysis Review
During the past decades, many novel agents have improved response and survival of patients with multiple myeloma. Nevertheless, it remains challenging when they suffer relapsing. Thus, novel therapeutic agents are needed. We aimed to assess the efficacy and safety of a novel agent panobinostat for patients with relapsed or/and refractory MM. A systematic literature review identified studies for clinical trials about panobinostat in patients with relapsed or/and refractory MM. We searched studies published between January 2000 and December 2015 in Pubmed, Ovid, EBSCO and the Cochrane library. Random-effect pooled estimates were calculated for overall response rate and rates of common adverse effects. The results showed 11 clinical trials including 700 patients with relapsed or/and refractory MM treated with panobinostat were identified. The ORR varied between 0.08 and 0.67. Pooled analyses showed the results that the ORR was 0.45 (95% CI: 0.31-0.59, I(2) = 90.5%, P = 0.000) for panobinostat combined with any other kind of drugs. The most common Grade3/4 adverse effects were thrombocytopenia, neutropenia, lymphopenia, anemia, diarrhea, fatigue, nausea and so on. In conclusion, based on our analyses, the regimen of panobinostat combining with other agents seems to be well tolerated and efficacious in patients with relapsed or/and refractory MM.
Topics: Antineoplastic Agents; Clinical Trials as Topic; Drug-Related Side Effects and Adverse Reactions; Humans; Hydroxamic Acids; Indoles; Multiple Myeloma; Panobinostat; Recurrence; Treatment Outcome
PubMed: 27270478
DOI: 10.1038/srep27361 -
Cells Jun 2021Compared to pancreatic adenocarcinoma (PDAC), pancreatic neuroendocrine tumors (PanNET) represent a rare and heterogeneous tumor entity. In addition to surgical...
Compared to pancreatic adenocarcinoma (PDAC), pancreatic neuroendocrine tumors (PanNET) represent a rare and heterogeneous tumor entity. In addition to surgical resection, several therapeutic approaches, including biotherapy, targeted therapy or chemotherapy are applicable. However, primary or secondary resistance to current therapies is still challenging. Recent genome-wide sequencing efforts in PanNET identified a large number of mutations in pathways involved in epigenetic modulation, including acetylation. Therefore, targeting epigenetic modulators in neuroendocrine cells could represent a new therapeutic avenue. Detailed information on functional effects and affected signaling pathways upon epigenetic targeting in PanNETs, however, is missing. The primary human PanNET cells NT-3 and NT-18 as well as the murine insulinoma cell lines beta-TC-6 (mouse) and RIN-T3 (rat) were treated with the non-selective histone-deacetylase (HDAC) inhibitor panobinostat (PB) and analyzed for functional effects and affected signaling pathways by performing Western blot, FACS and qPCR analyses. Additionally, NanoString analysis of more than 500 potentially affected targets was performed. In vivo immunohistochemistry (IHC) analyses on tumor samples from xenografts and the transgenic neuroendocrine Rip1Tag2-mouse model were investigated. PB dose dependently induced cell cycle arrest and apoptosis in neuroendocrine cells in human and murine species. HDAC inhibition stimulated redifferentiation of human primary PanNET cells by increasing mRNA-expression of somatostatin receptors (SSTRs) and insulin production. In addition to hyperacetylation of known targets, PB mediated pleitropic effects via targeting genes involved in the cell cycle and modulation of the JAK2/STAT3 axis. The HDAC subtypes are expressed ubiquitously in the existing cell models and in human samples of metastatic PanNET. Our results uncover epigenetic HDAC modulation using PB as a promising new therapeutic avenue in PanNET, linking cell-cycle modulation and pathways such as JAK2/STAT3 to epigenetic targeting. Based on our data demonstrating a significant impact of HDAC inhibition in clinical relevant in vitro models, further validation in vivo is warranted.
Topics: Animals; Cell Line, Tumor; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Mice; Neoplasm Proteins; Neuroectodermal Tumors; Pancreatic Neoplasms; Panobinostat; Rats
PubMed: 34204116
DOI: 10.3390/cells10061408 -
Cancer Investigation Apr 2023Anaplastic thyroid carcinoma (ATC) has poor prognosis, high mortality rate and lack of effective therapy. A synergic combination of PD-L1 antibody together with cell...
Anaplastic thyroid carcinoma (ATC) has poor prognosis, high mortality rate and lack of effective therapy. A synergic combination of PD-L1 antibody together with cell death promoting substances like deacetylase inhibitors (DACi) and multi-kinase inhibitors (MKI) could sensitize ATC cells and promote decay by autophagic cell death. The PD-L1-inhibitor atezolizumab synergized with panobinostat (DACi) and sorafenib (MKI) leading to significant reduction of the viability, measured by real time luminescence, of three different patient-derived primary ATC cells, of C643 cells and follicular epithelial thyroid cells too. administration of these compounds caused a significant over-expression of autophagy transcripts; meanwhile autophagy proteins were almost not detectable after the single administration of panobinostat, thus supporting a massive autophagy degradation process. Instead, the administration of atezolizumab caused an accumulation of autophagy proteins and the cleavage of the active caspases 8 and 3. Interestingly, only panobinostat and atezolizumab were able to exacerbate the autophagy process by increasing the synthesis, the maturation and final fusion with the lysosomes of the autophagosome vesicles. Despite ATC cells could be sensitized by atezolizumab the cleavage of the caspases, no reduction of cell proliferation or promotion of cell death was observed. The apoptosis assay evidenced the ability of panobinostat alone and in combination with atezolizumab to induce the phosphatidil serine exposure (early apoptosis) and further the secondary necrosis. Instead, sorafenib was only able to cause necrosis. The increase of caspases activity induced by atezolizumab, the apoptosis and autophagy processes promoted by panobinostat synergize thus promoting cell death in well-established and primary anaplastic thyroid cancer cells. The combined therapy could represent a future clinical application for the treatment of such lethal and untreatable solid cancer.
Topics: Autophagy; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Panobinostat; Sorafenib; Cell Line, Tumor; Antineoplastic Agents; Humans; Male; Aged; Aged, 80 and over; Cell Death; Spheroids, Cellular
PubMed: 36811581
DOI: 10.1080/07357907.2023.2183027 -
Advances in Therapy Nov 2016Panobinostat is an oral pan-histone deacetylase inhibitor developed by Novartis. Panobinostat acts via epigenetic modification and inhibition of the aggresome pathway.... (Review)
Review
UNLABELLED
Panobinostat is an oral pan-histone deacetylase inhibitor developed by Novartis. Panobinostat acts via epigenetic modification and inhibition of the aggresome pathway. In August 2015, the European Commission authorized panobinostat for use in combination with bortezomib and dexamethasone for the treatment of relapsed or relapsed and refractory multiple myeloma (MM) in patients who have received ≥2 prior regimens including bortezomib and an immunomodulatory drug. In January 2016, the National Institute for Health and Care Excellence recommended panobinostat for use in the same combination and patient population. The authorization and recommendation were based on results from the pivotal phase 3 PANORAMA 1 (NCT01023308) clinical trial, which demonstrated an improvement in median progression-free survival of 7.8 months for the three-drug combination compared with placebo plus bortezomib and dexamethasone in this patient population. This review will discuss the current treatment landscape for relapsed/refractory MM, the mechanism of action of panobinostat, clinical data supporting the European authorization, concerns about safety and strategies for mitigating toxicity, and how panobinostat fits into the current MM landscape in Europe.
FUNDING
Editorial support, funded by Novartis Pharmaceuticals.
Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Drug Resistance, Neoplasm; Drug-Related Side Effects and Adverse Reactions; Europe; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Indoles; Multiple Myeloma; Panobinostat; Recurrence
PubMed: 27677481
DOI: 10.1007/s12325-016-0413-7 -
Biochemical Pharmacology Feb 2024The majority of acute myeloid leukemia (AML) patients respond to intensive induction therapy, consisting of cytarabine (AraC) and an anthracycline, though more than half...
The majority of acute myeloid leukemia (AML) patients respond to intensive induction therapy, consisting of cytarabine (AraC) and an anthracycline, though more than half experience relapse. Relapsed/refractory (R/R) AML patients are difficult to treat, and their clinical outcomes remain dismal. Venetoclax (VEN) in combination with azacitidine (AZA) has provided a promising treatment option for R/R AML, though the overall survival (OS) could be improved (OS ranges from 4.3 to 9.1 months). Overexpression of c-Myc is associated with chemoresistance in AML. Histone deacetylase (HDAC) inhibitors have been shown to suppress c-Myc and enhance the antileukemic activity of VEN, as well as AZA, though combination of all three has not been fully explored. In this study, we investigated the HDAC inhibitor, panobinostat, in combination with VEN + AZA against AraC-resistant AML cells. Panobinostat treatment downregulated c-Myc and Bcl-xL and upregulated Bim, which enhanced the antileukemic activity of VEN + AZA against AraC-resistant AML cells. In addition, panobinostat alone and in combination with VEN + AZA suppressed oxidative phosphorylation and/or glycolysis in AraC-resistant AML cells. These findings support further development of panobinostat in combination with VEN + AZA for the treatment of AraC-resistant AML.
PubMed: 38373594
DOI: 10.1016/j.bcp.2024.116065 -
Current Hematologic Malignancy Reports Apr 2016The outcome of myeloma patients' dual refractory to lenalidomide and bortezomib is generally poor and represents a significant clinical challenge with a clear need for... (Review)
Review
The outcome of myeloma patients' dual refractory to lenalidomide and bortezomib is generally poor and represents a significant clinical challenge with a clear need for new therapeutic approaches. This has prompted the development of next-generation proteasome inhibitors and immunodulatory drugs (IMiDs), as well as new classes of drugs with novel mechanisms of action. As a result, several of these agents have received regulatory approval that have shown promising activity in the dual refractory setting including the second-generation proteasome inhibitor carfilzomib and third-generation IMiD pomalidomide. Moreover, the regulatory approval of several first-in-class drugs for myeloma such as the histone deacetylase (HDAC) inhibitor panobinostat and the anti-CD38 monoclonal antibody daratumumab has further broadened the therapeutic landscape for these patients. Collectively, these advances have provided new treatment strategies in dual refractory myeloma as well as important insights for the development of future studies with rationally designed drug combinations to target this challenging patient population.
Topics: Animals; Antineoplastic Agents; Drug Design; Humans; Multiple Myeloma; Recurrence
PubMed: 26898556
DOI: 10.1007/s11899-016-0312-7 -
Clinical Lymphoma, Myeloma & Leukemia Nov 2021Relapsed and refractory multiple myeloma (RRMM) presents a therapeutic challenge due to the development of drug resistance. Panobinostat is an oral histone deacetylase... (Review)
Review
Relapsed and refractory multiple myeloma (RRMM) presents a therapeutic challenge due to the development of drug resistance. Panobinostat is an oral histone deacetylase inhibitor (HDACi) that affects multiple cellular pathways and has demonstrated the ability to resensitize refractory-multiple myeloma cells in preclinical studies, as well as in patients with RRMM in clinical trials. Synergy of panobinostat with a number of different classes of antimyeloma drugs (proteasome inhibitors, immunomodulatory drugs and monoclonal antibodies) has also been shown. Panobinostat is a promising HDACi for the treatment of multiple myeloma. Here, we present a comprehensive review of preclinical and clinical studies of panobinostat.
Topics: Histone Deacetylase Inhibitors; Humans; Multiple Myeloma; Panobinostat
PubMed: 34340951
DOI: 10.1016/j.clml.2021.06.020 -
BMC Pharmacology & Toxicology Sep 2023The study aims to investigate the apoptotic effects of combining LBH589 and AM1241 (a selective CB2 receptor agonist) on cervical cancer cells and elucidating the...
PURPOSE
The study aims to investigate the apoptotic effects of combining LBH589 and AM1241 (a selective CB2 receptor agonist) on cervical cancer cells and elucidating the mechanism of this combined therapy, which may provide innovative strategies for treating this disease.
METHODS
The viability of the cervical cancer cells was measured by cell counting kit-8 (CCK-8) assay, and the synergistic effect was analyzed using SynergyFinder. Cell proliferation was tested by cell cloning. The apoptosis and reactive oxygen species (ROS) production in cervical cancer cells were analyzed by flow cytometry. Western blot and quantitative real-time PCR (qRT-PCR) were employed to determine changes in protein and gene levels of pathway-related factors.
RESULTS
By the results of cytotoxicity assay, SiHa cells were selected and treated with 0.1 μM LBH589 and 4 μM AM1241 for 24 h for subsequent experiments. The combination of both was synergistic as determined by bliss, ZIP, HSA and LOEWE synergy score. Plate cloning results showed that LBH589 combined with AM1241 inhibited the proliferation of cervical cancer cells compared to individual drug. Additionally, compared with LBH589 alone, the combination of LBH589 and AM1241 induced autophagy by increasing LC3II/LC3I and decreasing P62/GAPDH, leading to a significantly higher rate of apoptosis. Pharmacological inhibition of also inhibited apoptosis. Consistently, we found that the endoplasmic reticulum, DNA damage repair pathway were induced after co-administration. Furthermore, cellular ROS increased after co-administration, and apoptosis was inhibited by the addition of ROS scavenger.
CONCLUSION
LBH589 combined with AM1241 activated the endoplasmic reticulum emergency pathway, DNA damage repair signaling pathway, oxidative stress and autophagy pathway, ultimately promoting the apoptosis of cervical cancer cells. These findings suggest that the co-administration of LBH589 and AM1241 may be a new treatment plan for the treatment of cervical cancer.
Topics: Female; Humans; Uterine Cervical Neoplasms; Panobinostat; Reactive Oxygen Species; Apoptosis; Autophagy
PubMed: 37740231
DOI: 10.1186/s40360-023-00686-7 -
Clinical Advances in Hematology &... Nov 2017Multiple myeloma is a heterogeneous disease with a prognosis that varies with patient factors, disease burden, tumor biology, and treatments. Certain molecular... (Review)
Review
Multiple myeloma is a heterogeneous disease with a prognosis that varies with patient factors, disease burden, tumor biology, and treatments. Certain molecular abnormalities confer a worse prognosis and thus are considered high-risk. These include t(4;14), del(17p), t(14;16), t(14;20), hypodiploidy, and gain(1q)/del(1p). In our previous review in 2013, we discussed the effect of available therapies on prognosis in these high-risk patients. Since then, seven phase 3 clinical trials in relapsed myeloma with 1 to 3 lines of therapy have been conducted, resulting in the approval of panobinostat, ixazomib, daratumumab, and elotuzumab, as well as additional data on carfilzomib. In our current review of these studies, all the novel therapies resulted in an improvement in progression-free survival for high-risk patients, but none of the trials provided clear statistical evidence that they overcame high-risk status. Moreover, there are several limitations in the currently available data. For example, the patient's Revised International Staging System score is generally not reported, and even when it is reported, it is usually at the time of initial diagnosis rather than at the time of study entry. Furthermore, the methodology used to determine risk suffers from technologic issues. Finally, the clonal and allele burden and concurrent molecular abnormalities can affect risk status and prognosis. To determine the optimal therapy for high-risk patients, future clinical trials should provide standardized risk assessments for all patients in addition to hazard ratios for Kaplan-Meier survival curves of high-risk patients vs those of standard-risk patients to determine if high-risk status has truly been overcome by a novel agent.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Boron Compounds; Disease-Free Survival; Glycine; Humans; Hydroxamic Acids; Indoles; Kaplan-Meier Estimate; Multiple Myeloma; Oligopeptides; Panobinostat; Prognosis
PubMed: 29200420
DOI: No ID Found -
Pharmacological Research Mar 2017Deacetylase enzymes remove acetyl groups from histone and nonhistone proteins. Dysregulation of deacetylase activity is a hallmark of malignancy, including multiple... (Review)
Review
Deacetylase enzymes remove acetyl groups from histone and nonhistone proteins. Dysregulation of deacetylase activity is a hallmark of malignancy, including multiple myeloma (MM). Deacetylase inhibitors (DACi) cause epigenetic modification and inhibition of the aggresome pathway, resulting in death of MM cells. Panobinostat, a pan-DACi, has shown significant clinical benefit and is the first DACi approved for the treatment of MM. It is approved for use in combination with bortezomib and dexamethasone for the treatment of patients with relapsed or relapsed and refractory MM who have received ≥2 prior regimens including bortezomib and an immunomodulatory drug. Ricolinostat and ACY-241, which selectively inhibit HDAC6 and the aggresome pathway, are currently being studied in combination with dexamethasone and bortezomib or an immunomodulatory drug for the treatment of relapsed and refractory MM. In this review, we discuss the data from key clinical trials investigating deacetylase inhibitors as novel treatment options for MM.
Topics: Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Indoles; Multiple Myeloma; Panobinostat
PubMed: 27884726
DOI: 10.1016/j.phrs.2016.11.020