-
ELife Oct 2022As the most aggressive tumor, the outcome of pancreatic cancer (PACA) has not improved observably over the last decade. Anatomy-based TNM staging does not exactly...
As the most aggressive tumor, the outcome of pancreatic cancer (PACA) has not improved observably over the last decade. Anatomy-based TNM staging does not exactly identify treatment-sensitive patients, and an ideal biomarker is urgently needed for precision medicine. Based on expression files of 1280 patients from 10 multicenter cohorts, we screened 32 consensus prognostic genes. Ten machine-learning algorithms were transformed into 76 combinations, of which we selected the optimal algorithm to construct an artificial intelligence-derived prognostic signature (AIDPS) according to the average C-index in the nine testing cohorts. The results of the training cohort, nine testing cohorts, Meta-Cohort, and three external validation cohorts (290 patients) consistently indicated that AIDPS could accurately predict the prognosis of PACA. After incorporating several vital clinicopathological features and 86 published signatures, AIDPS exhibited robust and dramatically superior predictive capability. Moreover, in other prevalent digestive system tumors, the nine-gene AIDPS could still accurately stratify the prognosis. Of note, our AIDPS had important clinical implications for PACA, and patients with low AIDPS owned a dismal prognosis, higher genomic alterations, and denser immune cell infiltrates as well as were more sensitive to immunotherapy. Meanwhile, the high AIDPS group possessed observably prolonged survival, and panobinostat may be a potential agent for patients with high AIDPS. Overall, our study provides an attractive tool to further guide the clinical management and individualized treatment of PACA.
Topics: Humans; Gene Expression Profiling; Consensus; Artificial Intelligence; Panobinostat; Pancreatic Neoplasms; Machine Learning; Biomarkers
PubMed: 36282174
DOI: 10.7554/eLife.80150 -
Advanced Science (Weinheim,... Jul 2022Diffuse intrinsic pontine glioma (DIPG) is a rare and fatal pediatric brain tumor. Mutation of p53-induced protein phosphatase 1 (PPM1D) in DIPG cells promotes tumor...
Diffuse intrinsic pontine glioma (DIPG) is a rare and fatal pediatric brain tumor. Mutation of p53-induced protein phosphatase 1 (PPM1D) in DIPG cells promotes tumor cell proliferation, and inhibition of PPM1D expression in DIPG cells with PPM1D mutation effectively reduces the proliferation activity of tumor cells. Panobinostat effectively kills DIPG tumor cells, but its systemic toxicity and low blood-brain barrier (BBB) permeability limits its application. In this paper, a nano drug delivery system based on functionalized macrophage exosomes with panobinostat and PPM1D-siRNA for targeted therapy of DIPG with PPM1D mutation is prepared. The nano drug delivery system has higher drug delivery efficiency and better therapeutic effect than free drugs. In vivo and in vitro experimental results show that the nano drug delivery system can deliver panobinostat and siRNA across the BBB and achieve a targeted killing effect of DIPG tumor cells, resulting in the prolonged survival of orthotopic DIPG mice. This study provides new ideas for the delivery of small molecule drugs and gene drugs for DIPG therapy.
Topics: Animals; Astrocytoma; Brain Stem Neoplasms; Diffuse Intrinsic Pontine Glioma; Exosomes; Glioma; Humans; Macrophages; Mice; Panobinostat; Protein Phosphatase 2C; RNA, Small Interfering
PubMed: 35585670
DOI: 10.1002/advs.202200353 -
Clinical Lymphoma, Myeloma & Leukemia Jul 2022Despite the increasing number of treatment options available for multiple myeloma, relapse is still inevitable and there remains a critical unmet need for treatments for... (Review)
Review
Despite the increasing number of treatment options available for multiple myeloma, relapse is still inevitable and there remains a critical unmet need for treatments for patients with late-stage, highly refractory disease. In this review, we discuss currently approved treatment options for heavily pretreated patients with relapsed and refractory multiple myeloma, with a focus on the optimal management of patients with MM refractory to lenalidomide, bortezomib, and in some cases, daratumumab or an anti-CD38 monoclonal antibody. Data from recent clinical trials of immunomodulatory agents (pomalidomide), proteasome inhibitors (PIs; carfilzomib and ixazomib), monoclonal antibodies (elotuzumab, daratumumab, and isatuximab), and other novel therapies (including panobinostat-based therapy) are summarized. We also provide potential therapeutic strategies for patients according to different treatment histories, and include case studies to illustrate the practical use of various treatment options in a clinical setting. Regimens containing pomalidomide, elotuzumab, next-generation PIs, panobinostat, or selinexor may provide effective treatment options in patients with triple-refractory disease. The choice of agents used, and combinations thereof should be individualized as well as strategically planned from early- to late-stage relapse.
Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Lenalidomide; Multiple Myeloma; Neoplasm Recurrence, Local; Panobinostat; Proteasome Inhibitors
PubMed: 35148975
DOI: 10.1016/j.clml.2022.01.011 -
Annals of the Rheumatic Diseases Feb 2023Osteoarthritis (OA) features ageing-related defects in cellular homeostasis mechanisms in articular cartilage. These defects are associated with suppression of forkhead...
OBJECTIVES
Osteoarthritis (OA) features ageing-related defects in cellular homeostasis mechanisms in articular cartilage. These defects are associated with suppression of forkhead box O (FoxO) transcription factors. FoxO1 or FoxO3 deficient mice show early onset OA while FoxO1 protects against oxidative stress in chondrocytes and promotes expression of autophagy genes and the essential joint lubricant proteoglycan 4 (PRG4). The objective of this study was to identify small molecules that can increase FoxO1 expression.
METHODS
We constructed a reporter cell line with FoxO1 promoter sequences and performed high-throughput screening (HTS) of the Repurposing, Focused Rescue and Accelerated Medchem (ReFRAME) library . Hits from the HTS were validated and function was assessed in human chondrocytes, meniscus cells and synoviocytes and following administration to mice. The most promising hit, the histone deacetylase inhibitor (HDACI) panobinostat was tested in a murine OA model.
RESULTS
Among the top hits were HDACI and testing in human chondrocytes, meniscus cells and synoviocytes showed that panobinostat was the most promising compound as it increased the expression of autophagy genes and PRG4 while suppressing the basal and IL-1β induced expression of inflammatory mediators and extracellular matrix degrading enzymes. Intraperitoneal administration of panobinostat also suppressed the expression of mediators of OA pathogenesis induced by intra-articular injection of IL-1β. In a murine OA model, panobinostat reduced the severity of histological changes in cartilage, synovium and subchondral bone and improved pain behaviours.
CONCLUSION
Panobinostat has a clinically relevant activity profile and is a candidate for OA symptom and structure modification.
Topics: Humans; Mice; Animals; Forkhead Transcription Factors; Histone Deacetylase Inhibitors; Panobinostat; Osteoarthritis; Aging; Chondrocytes; Cartilage, Articular; Interleukin-1beta
PubMed: 36109140
DOI: 10.1136/ard-2021-221269 -
Cell Feb 2024CD4 T cells with latent HIV-1 infection persist despite treatment with antiretroviral agents and represent the main barrier to a cure of HIV-1 infection.... (Randomized Controlled Trial)
Randomized Controlled Trial
CD4 T cells with latent HIV-1 infection persist despite treatment with antiretroviral agents and represent the main barrier to a cure of HIV-1 infection. Pharmacological disruption of viral latency may expose HIV-1-infected cells to host immune activity, but the clinical efficacy of latency-reversing agents for reducing HIV-1 persistence remains to be proven. Here, we show in a randomized-controlled human clinical trial that the histone deacetylase inhibitor panobinostat, when administered in combination with pegylated interferon-α2a, induces a structural transformation of the HIV-1 reservoir cell pool, characterized by a disproportionate overrepresentation of HIV-1 proviruses integrated in ZNF genes and in chromatin regions with reduced H3K27ac marks, the molecular target sites for panobinostat. By contrast, proviruses near H3K27ac marks were actively selected against, likely due to increased susceptibility to panobinostat. These data suggest that latency-reversing treatment can increase the immunological vulnerability of HIV-1 reservoir cells and accelerate the selection of epigenetically privileged HIV-1 proviruses.
Topics: Humans; HIV Infections; HIV-1; Panobinostat; Proviruses; Virus Latency; Histone Deacetylase Inhibitors; Interferon-alpha
PubMed: 38367616
DOI: 10.1016/j.cell.2024.01.037 -
Drugs Apr 2015Novartis has developed oral and intravenous formulations of panobinostat (Farydak(®)), a histone deacetylase (HDAC) inhibitor, for the treatment of cancer. HDACs have... (Review)
Review
Novartis has developed oral and intravenous formulations of panobinostat (Farydak(®)), a histone deacetylase (HDAC) inhibitor, for the treatment of cancer. HDACs have important roles in maintaining chromatin structure and in regulating gene expression, including that of tumour suppressor genes, and thus represent valid targets in the search for cancer therapeutics. Oral panobinostat is approved in the US, as combination therapy with bortezomib and dexamethasone in patients with recurrent multiple myeloma who have received at least two prior treatment regimens, including bortezomib and an immunomodulatory agent. Regulatory submissions have been made for the use of combination therapy with panobinostat in patients with recurrent multiple myeloma in the EU and Japan. Panobinostat is in various stages of clinical development worldwide for a range of haematological and solid tumours. This article summarizes the milestones in the development of panobinostat leading to this first approval for multiple myeloma.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Drug Approval; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Indoles; Internationality; Molecular Structure; Multiple Myeloma; Panobinostat
PubMed: 25837990
DOI: 10.1007/s40265-015-0388-8 -
Current Opinion in HIV and AIDS Mar 2020To summarize the state of chronic, treated HIV infection and its contribution to accelerated aging, and to evaluate recent research relevant to the study and treatment... (Review)
Review
PURPOSE OF REVIEW
To summarize the state of chronic, treated HIV infection and its contribution to accelerated aging, and to evaluate recent research relevant to the study and treatment of aging and senescence.
RECENT FINDINGS
Chronic treated HIV-1 infection is associated with significant risk of end-organ impairment, non-AIDS-associated malignancies, and accelerated physiologic aging. Coupled with the chronologic aging of the HIV-1-positive population, the development of therapies that target these processes is of great clinical importance. Age-related diseases are partly the result of cellular senescence. Both immune and nonimmune cell subsets are thought to mediate this senescent phenotype, a state of stable cell cycle arrest characterized by sustained release of pro-inflammatory mediators. Recent research in the field of aging has identified a number of 'senotherapeutics' to combat aging-related diseases, pharmacologic agents that act either by selectively promoting the death of senescent cells ('senolytics') or modifying senescent phenotype ('senomorphics').
SUMMARY
Senescence is a hallmark of aging-related diseases that is characterized by stable cell cycle arrest and chronic inflammation. Chronic HIV-1 infection predisposes patients to aging-related illnesses and is similarly marked by a senescence-like phenotype. A better understanding of the role of HIV-1 in aging will inform the development of therapeutics aimed at eliminating senescent cells that drive accelerated physiologic aging.
Topics: Aging; Aniline Compounds; Antibiotics, Antineoplastic; Antineoplastic Agents; Antiretroviral Therapy, Highly Active; Bridged Bicyclo Compounds, Heterocyclic; CD4-CD8 Ratio; Cardiovascular Diseases; Cell Cycle Checkpoints; Cellular Senescence; HIV Infections; HIV-1; Histone Deacetylase Inhibitors; Humans; Inflammation; Janus Kinases; Nitriles; Panobinostat; Pyrazoles; Pyrimidines; Sirolimus; Sulfonamides; T-Lymphocyte Subsets
PubMed: 31833962
DOI: 10.1097/COH.0000000000000609 -
Clinical Pharmacokinetics Jan 2018Histone deacetylase (HDAC) inhibitors cause an increase in acetylation that leads to an increase in DNA transcription and accumulation of different proteins, reducing... (Review)
Review
Histone deacetylase (HDAC) inhibitors cause an increase in acetylation that leads to an increase in DNA transcription and accumulation of different proteins, reducing cell proliferation and inducing cell death. Panobinostat is a first-in-line HDAC inhibitor approved for treating multiple myeloma in combination with bortezomib and dexamethasone. It is a pan-deacetylase inhibitor and therefore inhibits not only HDAC but also other deacetylases. The main mechanism of action of panobinostat is to inhibit HDAC, which causes cell cycle arrest and apoptosis, leading to it being an antineoplastic drug. Pooled data of multiple-dose studies show that an oral dose of panobinostat 20 mg resulted in a maximum plasma concentration (C ) of 21.6 ng/mL approximately 1 h after administration, while doses between 10 and 30 mg resulted in dose proportional plasma levels. The absolute bioavailability of panobinostat is 21.4%, and it is moderately bound to plasma proteins. Renal impairment does not influence the intrinsic pharmacokinetics of panobinostat, however hepatic impairment causes an increase in the plasma concentrations of this drug. Therefore, starting treatment at lower doses could be considered in patients with mild to moderate hepatic impairment. Different ethnic backgrounds have an influence on the pharmacokinetics of panobinostat; however, due to major interindividual variability, no dose adjustment is recommended. The area under the concentration-time curve of panobinostat changes significantly under cytochrome P450 (CYP) 3A4 inhibitors, CYP3A4 and CYP2D6 inducers, and P-glycoprotein inhibitors. Panobinostat itself is a CYP2D6 inhibitor, which influences the plasma levels of the CYP2D6 substrate dexamethasone. The main side effects of panobinostat are diarrhea, peripheral neuropathy, asthenia and fatigue; hematologic side effects include neutropenia, thrombocytopenia, and lymphocytopenia.
Topics: Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Biological Availability; Bortezomib; Dexamethasone; Dose-Response Relationship, Drug; Histone Deacetylase Inhibitors; Humans; Multiple Myeloma; Panobinostat
PubMed: 28667459
DOI: 10.1007/s40262-017-0565-x -
Clinical Cancer Research : An Official... Nov 2015Panobinostat is a potent oral deacetylase inhibitor that alters gene expression through epigenetic mechanisms and inhibits protein degradation. It was recently approved... (Review)
Review
Panobinostat is a potent oral deacetylase inhibitor that alters gene expression through epigenetic mechanisms and inhibits protein degradation. It was recently approved by the FDA and EMA for use in combination with bortezomib and dexamethasone in patients with multiple myeloma who have received ≥2 prior regimens, including bortezomib and an immunomodulatory drug. Panobinostat was approved based on results from the phase III PANORAMA 1 trial in patients with relapsed or relapsed and refractory multiple myeloma, which showed that panobinostat plus bortezomib and dexamethasone significantly extended progression-free survival (median, 12.0 months) compared with placebo plus bortezomib and dexamethasone (median, 8.1 months; P < 0.0001). Additional ongoing trials are evaluating panobinostat in combination with other partners in the relapsed/refractory and newly diagnosed treatment settings. This review focuses on panobinostat and its mechanism of action, pharmacokinetics, and clinical data in the treatment of relapsed or relapsed and refractory multiple myeloma.
Topics: Antineoplastic Agents; Clinical Trials as Topic; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Indoles; Multiple Myeloma; Panobinostat; Treatment Outcome
PubMed: 26362997
DOI: 10.1158/1078-0432.CCR-15-0530