-
Nature Biotechnology Dec 2022Systematically identifying synergistic combinations of targeted agents and immunotherapies for cancer treatments remains difficult. In this study, we integrated...
Systematically identifying synergistic combinations of targeted agents and immunotherapies for cancer treatments remains difficult. In this study, we integrated high-throughput and high-content techniques-an implantable microdevice to administer multiple drugs into different sites in tumors at nanodoses and multiplexed imaging of tumor microenvironmental states-to investigate the tumor cell and immunological response signatures to different treatment regimens. Using a mouse model of breast cancer, we identified effective combinations from among numerous agents within days. In vivo studies in three immunocompetent mammary carcinoma models demonstrated that the predicted combinations synergistically increased therapeutic efficacy. We identified at least five promising treatment strategies, of which the panobinostat, venetoclax and anti-CD40 triple therapy was the most effective in inducing complete tumor remission across models. Successful drug combinations increased spatial association of cancer stem cells with dendritic cells during immunogenic cell death, suggesting this as an important mechanism of action in long-term breast cancer control.
Topics: Humans; Immunotherapy; Panobinostat; Antineoplastic Agents; Drug Delivery Systems; Neoplasms; Cell Line, Tumor
PubMed: 35788566
DOI: 10.1038/s41587-022-01379-y -
The Journal of Pharmacology and... Dec 2023Achieving adequate exposure of the free therapeutic agent at the target is a critical determinant of efficacious chemotherapy. With this in mind, a major challenge in...
Achieving adequate exposure of the free therapeutic agent at the target is a critical determinant of efficacious chemotherapy. With this in mind, a major challenge in developing therapies for central nervous system (CNS) tumors is to overcome barriers to delivery, including the blood-brain barrier (BBB). Panobinostat is a nonselective pan-histone deacetylase inhibitor that is being tested in preclinical and clinical studies, including for the treatment of pediatric medulloblastoma, which has a propensity for leptomeningeal spread and diffuse midline glioma, which can infiltrate into supratentorial brain regions. In this study, we examined the rate, extent, and spatial heterogeneity of panobinostat CNS distribution in mice. Transporter-deficient mouse studies show that panobinostat is a dual substrate of P-glycoprotein (P-gp) and breast cancer resistant protein (Bcrp), which are major efflux transporters expressed at the BBB. The CNS delivery of panobinostat was moderately limited by P-gp and Bcrp, and the unbound tissue-to-plasma partition coefficient of panobinostat was 0.32 and 0.21 in the brain and spinal cord in wild-type mice. In addition, following intravenous administration, panobinostat demonstrated heterogeneous distribution among brain regions, indicating that its efficacy would be influenced by tumor location or the presence and extent of leptomeningeal spread. Simulation using a compartmental BBB model suggests inadequate exposure of free panobinostat in the brain following a recommended oral dosing regimen in patients. Therefore, alternative approaches to CNS delivery may be necessary to have adequate exposure of free panobinostat for the treatment of a broad range of pediatric brain tumors. SIGNIFICANCE STATEMENT: This study shows that the central nervous system (CNS) penetration of panobinostat is limited by P-gp and Bcrp, and its efficacy may be limited by inadequate distribution to the tumor. Panobinostat has heterogeneous distribution into various brain regions, indicating that its efficacy might depend on the anatomical location of the tumors. These distributional parameters in the mouse CNS can inform both preclinical and clinical trial study design and may guide treatment for these devastating brain tumors in children.
Topics: Child; Humans; Animals; Mice; Panobinostat; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Neoplasm Proteins; Central Nervous System; Brain; Blood-Brain Barrier; Brain Neoplasms; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Membrane Transport Proteins
PubMed: 37827699
DOI: 10.1124/jpet.123.001826 -
American Journal of Health-system... Apr 2016The mechanism of action, pharmacodynamics, pharmacokinetics, clinical efficacy, interaction potential, adverse effects, and place in therapy of panobinostat are reviewed. (Review)
Review
PURPOSE
The mechanism of action, pharmacodynamics, pharmacokinetics, clinical efficacy, interaction potential, adverse effects, and place in therapy of panobinostat are reviewed.
SUMMARY
Panobinostat (Farydak, Novartis) is a novel pan-deacetylase inhibitor approved for use in combination with bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma (RRMM) who have received at least two regimens containing an immunomodulatory drug and bortezomib. National Comprehensive Cancer Network (NCCN) guidelines recommend the use of panobinostat plus bortezomib and dexamethasone as a preferred regimen for previously treated multiple myeloma (MM). A Phase III trial comparing panobinostat or placebo use in combination with bortezomib and dexamethasone demonstrated improved median progression-free survival in the panobinostat group (11.99 months [95% CI, 10.33-12.94 months] versus 8.08 months [95% CI, 7.56-9.23 months]; hazard ratio, 0.63 [95% CI, 0.52-0.76]; p < 0.0001), as well as a significantly higher rate of complete or near complete response (27.6% [95% CI, 23.2-32.4%] versus 15.7% [95% CI, 12.2-19.8%]; p = 0.00006). Common grade 3 or 4 laboratory abnormalities and adverse events associated with panobinostat include thrombocytopenia, lymphopenia, diarrhea, asthenia, fatigue, and peripheral neuropathy.
CONCLUSION
Panobinostat is a promising alternative to well-studied, NCCN-recommended regimens for the treatment of RRMM. It has demonstrated efficacy when used in combination with bortezomib and dexamethasone for the treatment of patients with MM who have received at least two prior regimens including bortezomib and an immunomodulatory agent. Despite the observed benefits, concern regarding toxicity may limit panobinostat use in practice.
Topics: Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Dexamethasone; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Indoles; Multiple Myeloma; Panobinostat; Recurrence; Treatment Outcome
PubMed: 27001985
DOI: 10.2146/ajhp150487 -
International Journal of Molecular... Jan 2024Endometrial cancer is the most frequent malignant tumor of the female reproductive tract but lacks effective therapy. EphA2, a receptor tyrosine kinase, is overexpressed...
Endometrial cancer is the most frequent malignant tumor of the female reproductive tract but lacks effective therapy. EphA2, a receptor tyrosine kinase, is overexpressed by various cancers including endometrial cancer and is associated with poor clinical outcomes. In preclinical models, EphA2-targeted drugs had modest efficacy. To discover potential synergistic partners for EphA2-targeted drugs, we performed a high-throughput drug screen and identified panobinostat, a histone deacetylase inhibitor, as a candidate. We hypothesized that combination therapy with an EphA2 inhibitor and panobinostat leads to synergistic cell death. Indeed, we found that the combination enhanced DNA damage, increased apoptosis, and decreased clonogenic survival in Ishikawa and Hec1A endometrial cancer cells and significantly reduced tumor burden in mouse models of endometrial carcinoma. Upon RNA sequencing, the combination was associated with downregulation of cell survival pathways, including senescence, cyclins, and cell cycle regulators. The Axl-PI3K-Akt-mTOR pathway was also decreased by combination therapy. Together, our results highlight EphA2 and histone deacetylase as promising therapeutic targets for endometrial cancer.
Topics: Animals; Female; Humans; Mice; Apoptosis; Cell Line, Tumor; Endometrial Neoplasms; Histone Deacetylase Inhibitors; Panobinostat; Phosphatidylinositol 3-Kinases; Molecular Targeted Therapy; Receptor, EphA2
PubMed: 38279277
DOI: 10.3390/ijms25021278 -
International Journal of Molecular... Dec 2022Histone deacetylase inhibitors show synergy with several genotoxic drugs. Herein, we investigated the biological impact of the combined treatment of panobinostat and...
Histone deacetylase inhibitors show synergy with several genotoxic drugs. Herein, we investigated the biological impact of the combined treatment of panobinostat and melphalan in multiple myeloma (MM). DNA damage response (DDR) parameters and the expression of DDR-associated genes were analyzed in bone marrow plasma cells (BMPCs) and peripheral blood mononuclear cells (PBMCs) from 26 newly diagnosed MM patients. PBMCs from 25 healthy controls (HC) were examined in parallel. Compared with the ex vivo melphalan-only treatment, combined treatment with panobinostat and melphalan significantly reduced the efficiency of nucleotide excision repair (NER) and double-strand-break repair (DSB/R), enhanced the accumulation of DNA lesions (monoadducts and DSBs), and increased the apoptosis rate only in patients’ BMPCs (all p < 0.001); marginal changes were observed in PBMCs from the same patients or HC. Accordingly, panobinostat pre-treatment decreased the expression levels of critical NER (DDB2, XPC) and DSB/R (MRE11A, PRKDC/DNAPKc, RAD50, XRCC6/Ku70) genes only in patients’ BMPCs; no significant changes were observed in PBMCs from patients or HC. Together, our findings demonstrate that panobinostat significantly increased the melphalan sensitivity of malignant BMPCs without increasing the melphalan sensitivity of PBMCs from the same patients, thus paving the way for combination therapies in MM with improved anti-myeloma efficacy and lower side effects.
Topics: Humans; Melphalan; Multiple Myeloma; Panobinostat; Leukocytes, Mononuclear; DNA Repair
PubMed: 36555311
DOI: 10.3390/ijms232415671 -
Current Topics in Medicinal Chemistry 2016Histone acetyl transferases (HATs) and histone deacetylases (HDACs) are antagonistic enzymes regulating the turnover of histone acetylation thereby governing gene... (Review)
Review
Histone acetyl transferases (HATs) and histone deacetylases (HDACs) are antagonistic enzymes regulating the turnover of histone acetylation thereby governing gene expression in a precise manner. Histone acetylation deregulation caused by aberrant expression of classical HDACs plays a crucial role in tumour onset and progression making these enzymes as striking targets for anticancer drugs and therapy. Small molecule inhibitors targetting HDACs (HDACi) have shown multiple biological effects including cell cycle arrest, differentiation and apoptosis in cancer cell models. The current review deals with the recently approved pan-HDAC inhibitor panobinostat (LBH589) and its antiproliferative activity against distinct cancers (breast, ovarian, lung and multiple myeloma). The intricate details about the different mechanisms triggered by panobinostat to exert cytotoxic effect in these cancers have also been provided. The article also highlights the different combination strategies of panobinostat which can be utilized for overcoming conventional therapy resistant cases and for achieving the enhanced therapeutic benefit from this marvelous inhibitor in the upcoming future.
Topics: Antineoplastic Agents; Cell Proliferation; Drug Screening Assays, Antitumor; Enzyme Inhibitors; Histone Acetyltransferases; Histone Deacetylases; Humans; Hydroxamic Acids; Indoles; Molecular Structure; Neoplasms; Panobinostat; Small Molecule Libraries; Structure-Activity Relationship
PubMed: 26268342
DOI: 10.2174/1568026615666150813145800 -
British Journal of Clinical Pharmacology Feb 2023Multiple myeloma accounts for over 10-15% of haematological malignancies. Continued molecular advances have resulted in the development of new drugs for treatment of... (Review)
Review
AIMS
Multiple myeloma accounts for over 10-15% of haematological malignancies. Continued molecular advances have resulted in the development of new drugs for treatment of multiple myeloma. Four drugs were approved by the Food and Drug Administration (FDA) in 2015, but their safety is not well defined. The aim of this study is to delineate the cardiovascular adverse events of these drugs.
METHODS
We reviewed the adverse cardiac events of newly approved FDA drugs since 2015 using the US FDA Adverse Events Reporting System (FAERS) database. We calculated the reporting odds ratio (ROR) with 95% confidence interval (CIs) for the drugs that have the highest incidence of cardiovascular adverse events.
RESULTS
Among the medications that have approved for multiple myeloma between 2015 and 2020, 4 novel drugs showed the highest incidence of cardiotoxicity. ROR (95% CI) for atrial fibrillation due to elotuzumab, ixazomib, daratumumab and panobinostat compared to other FAERS drugs was 5.8 (4.4-7.7), 1.9 (1.5-2.3), 4.8 (4.2-5.6) and 5.7 (4.1-8.1), respectively. The ROR (95% CI) for cardiac failure was 8.2 (6.4-10.5), 4.7 (4.1-5.4), 5.8 (4.9-6.7) and 5.6 (3.8-8.1) and ROR (95% CI) for coronary disease was 2.7 (1.9-3.9), 2.7 (2.3-3.2), 2.3 (1.9-2.8) and 4.6 (3.2-6.6) due to elotuzumab, ixazomib, daratumumab and panobinostat compared to all other drugs in FAERS.
CONCLUSION
Our results demonstrated that certain newly approved antimyeloma therapies are significantly associated with previously unknown cardiotoxicity. These results warrant further studies and highlight the importance of considering the cardiac history of patients with multiple myeloma when utilizing these novel agents.
Topics: Humans; United States; Multiple Myeloma; Pharmacovigilance; Cardiotoxicity; Panobinostat; Adverse Drug Reaction Reporting Systems; United States Food and Drug Administration
PubMed: 35996166
DOI: 10.1111/bcp.15499 -
Best Practice & Research. Clinical... 2015Despite the steady increase in the number of stem cell transplants performed since 1980 and improvements in survival rates, disease relapse remains the major cause of... (Review)
Review
Despite the steady increase in the number of stem cell transplants performed since 1980 and improvements in survival rates, disease relapse remains the major cause of death after HLA matched sibling and unrelated donor transplants for acute myeloid leukemia (AML). Given this situation, maintenance therapy after transplant may be an appropriate strategy to reduce the relapse rate and prolong survival. A number of agents are being investigated as maintenance therapy after stem cell transplant in AML patients, including azacitidine, decitabine, and other agents. This paper focuses on the role of maintenance treatment to reduce the risk of relapse after transplant.
Topics: Antineoplastic Agents; Azacitidine; Benzothiazoles; Decitabine; Hematopoietic Stem Cell Transplantation; Humans; Hydroxamic Acids; Indoles; Leukemia, Myeloid, Acute; Maintenance Chemotherapy; Niacinamide; Panobinostat; Phenylurea Compounds; Recurrence; Siblings; Sorafenib; Survival Analysis; Transplantation, Homologous; Unrelated Donors
PubMed: 26590769
DOI: 10.1016/j.beha.2015.10.009 -
Journal of Oncology Pharmacy Practice :... Apr 2019Multiple myeloma is a plasma cell neoplasm that has seen impressive improvements in outcomes in recent years with combination therapies, such as proteasome inhibitors... (Review)
Review
Multiple myeloma is a plasma cell neoplasm that has seen impressive improvements in outcomes in recent years with combination therapies, such as proteasome inhibitors and immunomodulatory drugs. Histone deacetylase inhibition is an additional unique mechanism of action with established biological relevance in multiple myeloma. Panobinostat is the first histone deacetylase inhibitor indicated for the treatment of relapsed/refractory multiple myeloma in patients who have received at least two prior regimens, including bortezomib and an immunomodulatory agent. While the addition of panobinostat to bortezomib and dexamethasone has demonstrated response and progression-free survival benefits, the incidence and severity of adverse events associated with it can create a challenge for clinicians and patients. Specifically, diarrhea, myelosuppression, an increased risk for infectious complications, cardiotoxicity, and nausea/vomiting may be seen with use. The frequency and grade of adverse event occurrence may differ between doses and schedule of panobinostat as well as with different companion therapies and routes. Herein we discuss the incidence, severity, and practical management of adverse events associated with panobinostat in the treatment of relapsed/refractory multiple myeloma.
Topics: Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Histone Deacetylase Inhibitors; Humans; Incidence; Multiple Myeloma; Panobinostat
PubMed: 30060709
DOI: 10.1177/1078155218788706 -
Cancer Science Nov 2016Histone deacetylases (HDACs) critically regulate gene expression by determining the acetylation status of histones. Studies have increasingly focused on the activities... (Review)
Review
Histone deacetylases (HDACs) critically regulate gene expression by determining the acetylation status of histones. Studies have increasingly focused on the activities of HDACs, especially involving non-histone proteins, and their various biological effects. Aberrant HDAC expression observed in several kinds of human tumors makes HDACs potential targets for cancer treatment. Several preclinical studies have suggested that HDAC inhibitors show some efficacy in the treatment of acute myelogenous leukemia with AML1-ETO, which mediates transcriptional repression through its interaction with a complex including HDAC1. Recurrent mutations in epigenetic regulators are found in T-cell lymphomas (TCLs), and HDAC inhibitors and hypomethylating agents were shown to act cooperatively in the treatment of TCLs. Preclinical modeling has suggested that persistent activation of the signal transducer and activator of transcription signaling pathway could serve as a useful biomarker of resistance to HDAC inhibitor in patients with cutaneous TCL. Panobinostat, a pan-HDAC inhibitor, in combination with bortezomib and dexamethasone, has achieved longer progression-free survival in patients with relapsed/refractory multiple myeloma (MM) than the placebo in combination with bortezomib and dexamethasone. Panobinostat inhibited MM cell growth by degrading protein phosphatase 3 catalytic subunit α (PPP3CA), a catalytic subunit of calcineurin. This degradation was suggested to be mediated by the blockade of the chaperone function of heat shock protein 90 due to HDAC6 inhibition. Aberrant PPP3CA expression in advanced MM indicated a possible correlation between high PPP3CA expression and the pathogenesis of MM. Furthermore, PPP3CA was suggested as a common target of panobinostat and bortezomib.
Topics: Animals; Calcineurin; Hematologic Neoplasms; Histone Deacetylase Inhibitors; Humans; Leukemia, Myeloid, Acute; Lymphoma, T-Cell; Multiple Myeloma
PubMed: 27554046
DOI: 10.1111/cas.13062