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Nature Communications Dec 2023The development of latency reversing agents that potently reactivate HIV without inducing global T cell activation would benefit the field of HIV reservoir research and...
The development of latency reversing agents that potently reactivate HIV without inducing global T cell activation would benefit the field of HIV reservoir research and could pave the way to a functional cure. Here, we explore the reactivation capacity of a lipid nanoparticle containing Tat mRNA (Tat-LNP) in CD4 T cells from people living with HIV undergoing antiretroviral therapy (ART). When combined with panobinostat, Tat-LNP induces latency reversal in a significantly higher proportion of latently infected cells compared to PMA/ionomycin (≈ 4-fold higher). We demonstrate that Tat-LNP does not alter the transcriptome of CD4 T cells, enabling the characterization of latently infected cells in their near-native state. Upon latency reversal, we identify transcriptomic differences between infected cells carrying an inducible provirus and non-infected cells (e.g. LINC02964, GZMA, CCL5). We confirm the transcriptomic differences at the protein level and provide evidence that the long non-coding RNA LINC02964 plays a role in active HIV infection. Furthermore, p24+ cells exhibit heightened PI3K/Akt signaling, along with downregulation of protein translation, suggesting that HIV-infected cells display distinct signatures facilitating their long-term persistence. Tat-LNP represents a valuable research tool for in vitro reservoir studies as it greatly facilitates the in-depth characterization of HIV reservoir cells' transcriptome and proteome profiles.
Topics: Virus Latency; Gene Products, tat; RNA, Viral; Nanoparticles; HIV Infections; Panobinostat; Antiretroviral Therapy, Highly Active; CD4-Positive T-Lymphocytes; CD4 Antigens; HIV-1; Proviruses; Single-Cell Gene Expression Analysis; HIV Core Protein p24; RNA, Long Noncoding; Cells, Cultured; Humans; Ionomycin
PubMed: 38110433
DOI: 10.1038/s41467-023-44020-5 -
Frontiers in Pharmacology 2023Afatinib is an irreversible epidermal growth factor receptor tyrosine kinase inhibitor, and it plays a role in hepatocellular carcinoma (LIHC). This study aimed to...
Afatinib is an irreversible epidermal growth factor receptor tyrosine kinase inhibitor, and it plays a role in hepatocellular carcinoma (LIHC). This study aimed to screen a key gene associated with afatinib and identify its potential candidate drugs. We screened afatinib-associated differential expressed genes based on transcriptomic data of LIHC patients from The Cancer Genome Atlas, Gene Expression Omnibus, and the Hepatocellular Carcinoma Database (HCCDB). By using the Genomics of Drug Sensitivity in Cancer 2 database, we determined candidate genes using analysis of the correlation between differential genes and half-maximal inhibitory concentration. Survival analysis of candidate genes was performed in the TCGA dataset and validated in HCCDB18 and GSE14520 datasets. Immune characteristic analysis identified a key gene, and we found potential candidate drugs using CellMiner. We also evaluated the correlation between the expression of ADH1B and its methylation level. Furthermore, Western blot analysis was performed to validate the expression of ADH1B in normal hepatocytes LO2 and LIHC cell line HepG2. We screened eight potential candidate genes (ASPM, CDK4, PTMA, TAT, ADH1B, ANXA10, OGDHL, and PON1) associated with afatinib. Patients with higher ASPM, CDK4, PTMA, and TAT exhibited poor prognosis, while those with lower ADH1B, ANXA10, OGDHL, and PON1 had unfavorable prognosis. Next, ADH1B was identified as a key gene negatively correlated with the immune score. The expression of ADH1B was distinctly downregulated in tumor tissues of pan-cancer. The expression of ADH1B was negatively correlated with ADH1B methylation. Small-molecule drugs panobinostat, oxaliplatin, ixabepilone, and seliciclib were significantly associated with ADH1B. The protein level of ADH1B was significantly downregulated in HepG2 cells compared with LO2 cells. Our study provides ADH1B as a key afatinib-related gene, which is associated with the immune microenvironment and can be used to predict the prognosis of LIHC. It is also a potential target of candidate drugs, sharing a promising approach to the development of novel drugs for the treatment of LIHC.
PubMed: 37229243
DOI: 10.3389/fphar.2023.1166454 -
Biomedicines Jan 2020Novel treatment regimens are required for castration-resistant prostate cancers (CRPCs) that become unresponsive to standard treatments, such as docetaxel and... (Review)
Review
Novel treatment regimens are required for castration-resistant prostate cancers (CRPCs) that become unresponsive to standard treatments, such as docetaxel and enzalutamide. Histone deacetylase (HDAC) inhibitors showed promising results in hematological malignancies, but they failed in solid tumors such as prostate cancer, despite the overexpression of HDACs in CRPC. Four HDAC inhibitors, vorinostat, pracinostat, panobinostat and romidepsin, underwent phase II clinical trials for prostate cancers; however, phase III trials were not recommended due to a majority of patients exhibiting either toxicity or disease progression. In this review, the pharmacodynamic reasons for the failure of HDAC inhibitors were assessed and placed in the context of the advancements in the understanding of CRPCs, HDACs and resistance mechanisms. The review focuses on three themes: evolution of androgen receptor-negative prostate cancers, development of resistance mechanisms and differential effects of HDACs. In conclusion, advancements can be made in this field by characterizing HDACs in prostate tumors more extensively, as this will allow more specific drugs catering to the specific HDAC subtypes to be designed.
PubMed: 32019149
DOI: 10.3390/biomedicines8020022 -
Neuro-oncology Mar 2021Diffuse midline gliomas (DMGs), including diffuse intrinsic pontine gliomas (DIPGs), have a dismal prognosis, with less than 2% surviving 5 years postdiagnosis. The...
BACKGROUND
Diffuse midline gliomas (DMGs), including diffuse intrinsic pontine gliomas (DIPGs), have a dismal prognosis, with less than 2% surviving 5 years postdiagnosis. The majority of DIPGs and all DMGs harbor mutations altering the epigenetic regulatory histone tail (H3 K27M). Investigations addressing DMG epigenetics have identified a few promising drugs, including the HDAC inhibitor (HDACi) panobinostat. Here, we use clinically relevant DMG models to identify and validate other effective HDACi and their biomarkers of response.
METHODS
HDAC inhibitors were tested across biopsy-derived treatment-naïve in vitro and in vivo DMG models with biologically relevant radiation resistance. RNA sequencing was performed to define and compare drug efficacy and to map predictive biomarkers of response.
RESULTS
Quisinostat and romidepsin showed efficacy with low nanomolar half-maximal inhibitory concentration (IC50) values (~50 and ~5 nM, respectively). Comparative transcriptome analyses across quisinostat, romidepsin, and panobinostat showed a greater degree of shared biological effects between quisinostat and panobinostat, and less overlap with romidepsin. However, some transcriptional changes were consistent across all 3 drugs at similar biologically effective doses, such as overexpression of troponin T1 slow skeletal type (TNNT1) and downregulation of collagen type 20 alpha 1 chain (COL20A1), identifying these as potential vulnerabilities or on-target biomarkers in DMG. Quisinostat and romidepsin significantly (P < 0.0001) inhibited in vivo tumor growth.
CONCLUSIONS
Our data highlight the utility of treatment-naïve biopsy-derived models; establishes quisinostat and romidepsin as effective in vivo; illuminates potential mechanisms and/or biomarkers of DMG cell lethality due to HDAC inhibition; and emphasizes the need for brain tumor-penetrant versions of potentially efficacious agents.
Topics: Biopsy; Brain Stem Neoplasms; Glioma; Histones; Humans; Mutation; Panobinostat
PubMed: 33130903
DOI: 10.1093/neuonc/noaa249 -
Seminars in Oncology 2023Panobinostat is an oral pan histone-deacetylase inhibitor used in the treatment of relapsed and refractory multiple myeloma. Previously published studies of panobinostat...
Panobinostat is an oral pan histone-deacetylase inhibitor used in the treatment of relapsed and refractory multiple myeloma. Previously published studies of panobinostat demonstrated synergy with bortezomib but included few patients exposed to newer agent combinations (ie, panobinostat plus daratumumab or carfilzomib). Here, we report outcomes of panobinostat-based combinations at an academic medical center among patients whose disease had been heavily pretreated with modern agents. We retrospectively analyzed 105 patients with myeloma treated with panobinostat at The Mount Sinai Hospital in New York City between October 2012 and October 2021. These patients had a median age of 65 (range 37-87) and had received a median of 6 prior lines of therapy while in 53% the disease was classified as triple class refractory and in 54% the disease had high-risk cytogenetics. Panobinostat was most commonly utilized at 20 mg (64.8%) as part of a triplet (61.0%) or quadruplet (30.5%). Aside from steroids, panobinostat was most commonly administered in combination with lenalidomide, pomalidomide, carfilzomib, and daratumumab in descending order of frequency. Among the 101 response-evaluable patients, the overall response rate was 24.8%, clinical benefit rate (≥minimal response) was 36.6%, and median progression-free survival was 3.4 months. Median overall survival was 19.1 months. The most common toxicities ≥grade 3 were hematologic, primarily neutropenia (34.3%), thrombocytopenia (27.6%), and anemia (19.1%). Panobinostat-based combinations produced modest response rates in patients with heavily pretreated multiple myeloma, over half of whom had triple-class refractory disease. Panobinostat warrants continued investigation as a tolerable oral option for recapturing responses in patients whose disease has progressed after receipt of standard-of-care therapies.
Topics: Humans; Panobinostat; Multiple Myeloma; Retrospective Studies; Indoles; Hydroxamic Acids; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone
PubMed: 37005144
DOI: 10.1053/j.seminoncol.2023.03.006 -
Frontiers in Genetics 2021Somatic mutations in histone encoding genes result in gross alterations in the epigenetic landscape. Diffuse intrinsic pontine glioma (DIPG) is a pediatric high-grade... (Review)
Review
Somatic mutations in histone encoding genes result in gross alterations in the epigenetic landscape. Diffuse intrinsic pontine glioma (DIPG) is a pediatric high-grade glioma (pHGG) and one of the most challenging cancers to treat, with only 1% surviving for 5 years. Due to the location in the brainstem, DIPGs are difficult to resect and rapidly turn into a fatal disease. Over 80% of DIPGs confer mutations in genes coding for histone 3 variants (H3.3 or H3.1/H3.2), with lysine to methionine substitution at position 27 (H3K27M). This results in a global decrease in H3K27 trimethylation, increased H3K27 acetylation, and widespread oncogenic changes in gene expression. Epigenetic modifying drugs emerge as promising candidates to treat DIPG, with histone deacetylase (HDAC) inhibitors taking the lead in preclinical and clinical studies. However, some data show the evolving resistance of DIPGs to the most studied HDAC inhibitor panobinostat and highlight the need to further investigate its mechanism of action. A new forceful line of research explores the simultaneous use of multiple inhibitors that could target epigenetically induced changes in DIPG chromatin and enhance the anticancer response of single agents. In this review, we summarize the therapeutic approaches against H3K27M-expressing pHGGs focused on targeting epigenetic dysregulation and highlight promising combinatorial drug treatments. We assessed the effectiveness of the epigenetic drugs that are already in clinical trials in pHGGs. The constantly expanding understanding of the epigenetic vulnerabilities of H3K27M-expressing pHGGs provides new tumor-specific targets, opens new possibilities of therapy, and gives hope to find a cure for this deadly disease.
PubMed: 34646308
DOI: 10.3389/fgene.2021.742561 -
Pharmaceuticals (Basel, Switzerland) Jul 2021Among the well-established alterations contributing to prostate cancer (PCa) pathogenesis, epigenetics is an important player in its development and aggressive disease...
Among the well-established alterations contributing to prostate cancer (PCa) pathogenesis, epigenetics is an important player in its development and aggressive disease state. Moreover, since no curative therapies are available for advanced stage disease, there is an urgent need for novel therapeutic strategies targeting this subset of patients. Thus, we aimed to evaluate the combined antineoplastic effects of DNA methylation inhibitor hydralazine and histone deacetylase inhibitors panobinostat and valproic acid in several prostate cell lines. The effect of these drugs was assessed in four PCa (LNCaP, 22Rv1, DU145 and PC-3) cell lines, as well as in non-malignant epithelial (RWPE-1) and stromal (WPMY-1) cell lines, using several assays to evaluate cell viability, apoptosis, proliferation, DNA damage and clonogenic potential. We found that exposure to each epidrug separately reduced viability of all PCa cells in a dose-dependent manner and that combined treatments led to synergic growth inhibitory effects, impacting also on colony formation, invasion, apoptotic and proliferation rates. Interestingly, antitumoral effects of combined treatment were particularly expressive in DU145 cells. We concluded that hydralazine and panobinostat attenuate malignant properties of PCa cells, constituting a potential therapeutic tool to counteract PCa progression.
PubMed: 34358096
DOI: 10.3390/ph14070670 -
Cancers Oct 2021Novel treatments are needed to address the lack of options for patients with relapsed or refractory multiple myeloma. Even though immunotherapy-based treatments have... (Review)
Review
Novel treatments are needed to address the lack of options for patients with relapsed or refractory multiple myeloma. Even though immunotherapy-based treatments have revolutionized the field in recent years, offering new opportunities for patients, there is still no curative therapy. Thus, non-immunologic agents, which have proven effective for decades, are still central to the treatment of multiple myeloma, especially for advanced disease. Building on their efficacy in myeloma, the development of proteasome inhibitors and immunomodulatory drugs has been pursued, and has led to the emergence of a novel generation of agents (e.g., carfilzomib, ixazomib, pomalidomide). The use of alkylating agents is decreasing in most treatment regimens, but melflufen, a peptide-conjugated alkylator with a completely new mechanism of action, offers interesting opportunities. Moreover, with the identification of novel targets, new drug classes have entered the myeloma armamentarium, such as XPO1 inhibitors (selinexor), HDAC inhibitors (panobinostat), and anti-BCL-2 agents (venetoclax). New pathways are still being explored, especially the possibility of a mutation-driven strategy, as biomarkers and targeted treatments are increasing. Though multiple myeloma is still considered incurable, the treatment options are expanding and are progressively becoming more diverse, largely because of the continuous development of non-immunologic agents.
PubMed: 34680358
DOI: 10.3390/cancers13205210 -
Experimental Hematology Jan 2020Gemcitabine (Gem), busulfan (Bu), and melphalan (Mel) are used for hematopoietic stem cell transplantation. To further improve their efficacy, a preclinical study on...
Gemcitabine (Gem), busulfan (Bu), and melphalan (Mel) are used for hematopoietic stem cell transplantation. To further improve their efficacy, a preclinical study on their synergism with the histone deacetylase inhibitor panobinostat (Pano) and the BCL2 inhibitor venetoclax/ABT199 was performed. Multiple myeloma cell lines MM.1R and MC/CAR were exposed to ∼IC levels of the drugs. Synergistic cytotoxicity was observed in cells exposed to the five-drug combination as indicated by combination indexes <1, supported by ∼86% inhibition of proliferation and ∼84% annexin V positivity in MM.1R and ∼58% inhibition of proliferation and ∼46% annexin V positivity in MC/CAR cells. Activation of the DNA damage response and apoptosis were suggested by a modest increase in the phosphorylation of ATM and its substrates; significant cleavage of PARP1, caspase 3, and heat shock protein 90; DNA fragmentation; mitochondrial membrane depolarization; and reactive oxygen species production. The five-drug combination significantly decreased the levels of PI3K, AKT, mTOR, RAPTOR, P-P70S6K, and eIF2α, with concomitant increases in P-AMPK and its substrate Tuberin/TSC2, suggesting that the mTOR signaling pathway was compromised. Endoplasmic reticulum stress through activation of the unfolded protein response was also observed as suggested by increases in the levels of calnexin, BiP/GRP78, ERO1-Lα, and protein disulfide isomerase, which may relate to venetoclax-mediated inhibition of BCL2 in the endoplasmic reticulum. This is the first report on the effects of a venetoclax-containing regimen on the unfolded protein response. These results provide a rationale to propose a clinical trial on use of Gem + Bu + Mel + Pano + Venetoclax as part of a conditioning regimen for multiple myeloma patients undergoing autologous hematopoietic stem cell transplantation.
Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Busulfan; Cell Line, Tumor; Cytotoxins; DNA Fragmentation; Deoxycytidine; Drug Screening Assays, Antitumor; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Humans; Melphalan; Membrane Potential, Mitochondrial; Multiple Myeloma; Neoplasm Proteins; Panobinostat; Signal Transduction; Sulfonamides; Gemcitabine
PubMed: 31954171
DOI: 10.1016/j.exphem.2020.01.003 -
PloS One 2022The combination of panobinostat, bortezomib and dexamethasone (PanBorDex) is available as a treatment option for relapsed refractory multiple myeloma (RRMM) based on the...
The combination of panobinostat, bortezomib and dexamethasone (PanBorDex) is available as a treatment option for relapsed refractory multiple myeloma (RRMM) based on the PANORAMA-1 trial which investigated this triplet in early relapse. In routine clinical care, PanBorDex is used primarily in later relapses and is commonly administered in attenuated dosing schedules to mitigate the treatment-related toxicity. We set out to evaluate efficacy and safety outcomes with PanBorDex later in the disease course and evaluate the role of attenuated dosing schedules. This was a retrospective evaluation of patients treated in routine clinical practice between 2016-2019 across seven heamatology centres in the UK; patients who received at least one dose of PanBorDex were eligible for inclusion. The dosing schedule of panobinostat (10mg, 15mg or 20mg, twice or three times a week) and bortezomib (0.7mg/m2, 1mg/m2 or 1.3mg/m2 once or twice weekly) was as per treating physician choice. Patients received treatment until disease progression or unacceptable toxicity. The primary outcome is response rates according to IMWG criteria. Key secondary endpoints include progression-free survival (PFS) and overall survival (OS). Other secondary endpoints include rates of adverse events according to CTCAE criteria. In total, 61 patients were eligible for inclusion and received PanBorDex primarily as ≥5th line of treatment. One third of patients received PanBorDex at full dose, for the remaining two thirds, treatment was given in reduced dose intensities. The overall response rate was 44.2%, including 14.7% very good partial response (VGPR) rates; 68.8% of patients derived clinical benefit with stable disease or better. The median PFS was 3.4 months; non-refractory patients and those who achieved VGPR benefited from prolonged PFS of 11.4 months and 17.7 months, respectively. The median OS was 9.5 months. The triplet was associated with 45% and 18% incidence of grade 3-4 thrombocytopenia and diarrhea, respectively.
Topics: Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Humans; Multiple Myeloma; Panobinostat; Retrospective Studies; United Kingdom
PubMed: 35797277
DOI: 10.1371/journal.pone.0270854