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Panobinostat

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https://www.readbyqxmd.com/read/29774521/patient-reported-outcomes-of-multiple-myeloma-patients-treated-with-panobinostat-after-%C3%A2-2-lines-of-therapy-based-on-the-international-phase-3-randomized-double-blind-placebo-controlled-panorama-1-trial
#1
Paul G Richardson, Robert L Schlossman, Anuja N Roy, Ashok Panneerselvam, Suddhasatta Acharyya, Monika Sopala, Sagar Lonial
The phase 3 PANORAMA-1 trial led to regulatory approvals of panobinostat (PAN) in combination with bortezomib (BTZ) and dexamethasone (DEX) for the treatment of multiple myeloma after ≥2 prior regimens, including BTZ and an immunomodulatory drug. Patient-reported outcomes (PROs) were assessed in PANORAMA-1, with data available for 73 patients in the PAN + BTZ + DEX arm and 74 patients in the placebo (PBO) + BTZ + DEX arm. Per the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), global health status/quality of life (QoL) scores initially declined with PAN + BTZ + DEX during the first 24 weeks before approaching baseline scores and remaining steady during the next 24 weeks, with no difference between arms at Week 48...
May 17, 2018: British Journal of Haematology
https://www.readbyqxmd.com/read/29774113/ezh2-inhibitors-sensitize-myeloma-cell-lines-to-panobinostat-resulting-in-unique-combinatorial-transcriptomic-changes
#2
Taylor Harding, Jessica Swanson, Brian Van Ness
Multiple myeloma (MM) remains a largely incurable hematologic cancer due to an inability to broadly target inevitable drug-resistant relapse. Epigenetic abnormalities are abundantly present in multiple myeloma and have increasingly demonstrated critical roles for tumor development and relapse to standard therapies. Accumulating evidence suggests that the histone methyltransferase EZH2 is aberrantly active in MM. We tested the efficacy of EZH2 specific inhibitors in a large panel of human MM cell lines (HMCLs) and found that only a subset of HMCLs demonstrate single agent sensitivity despite ubiquitous global H3K27 demethylation...
April 24, 2018: Oncotarget
https://www.readbyqxmd.com/read/29764852/combined-hdac-and-bromodomain-protein-inhibition-reprograms-tumor-cell-metabolism-and-elicits-synthetic-lethality-in-glioblastoma
#3
Yiru Zhang, Chiaki Tsuge Ishida, Wataru Ishida, Sheng-Fu L Lo, Junfei Zhao, Chang Shu, Elena Bianchetti, Giulio Kleiner, Maria Sanchez-Quintero, Catarina M Quinzii, Mike-Andrew Westhoff, Georg Karpel-Massler, Peter Canoll, Markus D Siegelin
PURPOSE: Glioblastoma remain a challenge in oncology in part due to tumor heterogeneity. EXPERIMENTAL DESIGN: Patient-derived xenograft and stem-like glioblastoma cells were used as the primary model systems. RESULTS: Based on a transcriptome and subsequent gene set enrichment analysis (GSEA), we show by using clinically validated compounds that combined histone deacetylase (HDAC) inhibition and Bromodomain protein (BRD) inhibition results in pronounced synergistic reduction in cellular viability in patient-derived xenograft and stem-like glioblastoma cells...
May 15, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29762469/individualised-multimodal-treatment-strategies-for-anaplastic-and-poorly-differentiated-thyroid-cancer
#4
Sabine Wächter, Annette Wunderlich, Silvia Roth, Ioannis Mintziras, Elisabeth Maurer, Sebastian Hoffmann, Frederik A Verburg, Sebastian A Fellinger, Katharina Holzer, Detlef K Bartsch, Pietro Di Fazio
The prognosis of anaplastic (ATC) and poorly differentiated thyroid cancer (PDTC) is poor, due to their radioiodine refractoriness (RAI-R), high metastatic potential and current lack of effective treatment strategies. We aimed to examine the efficacy of the tyrosine kinase inhibitors (TKIs) sorafenib and selumetinib and the histone deacetylase inhibitor (HDACI) panobinostat in patient-derived tumor tissue (PDTT) of ATCs/PDTCs, the expression of sodium iodide symporter ( NIS ) and radioiodine up-take (RAI-U)...
May 15, 2018: Journal of Clinical Medicine
https://www.readbyqxmd.com/read/29709701/co-targeting-of-bet-proteins-and-hdacs-as-a-novel-approach-to-trigger-apoptosis-in-rhabdomyosarcoma-cells
#5
Julius C Enßle, Cathinka Boedicker, Marek Wanior, Meike Vogler, Stefan Knapp, Simone Fulda
Histone acetylation marks exert essential functions in regulating gene expression. These marks are written by histone acetyltransferases (HATs), removed by histone deacetylases (HDACs) and read by e.g. BET proteins. While BET inhibitors are promising new anticancer drugs, little is yet known on their antitumor activity in rhabdomyosarcoma (RMS). We therefore investigated the efficacy of the prototypic BET inhibitor JQ1 alone or in combination with other epigenetic modifiers, namely HDAC inhibitors (HDACIs)...
April 27, 2018: Cancer Letters
https://www.readbyqxmd.com/read/29670210/phase-i-trial-of-histone-deacetylase-inhibitor-panobinostat-in-addition-to-glucocorticoids-for-primary-therapy-of-acute-graft-versus-host-disease
#6
Lia Perez, Hugo Fernandez, Pedro Horna, Marcie Riches, Frederick Locke, Teresa Field, John Powers, Eva Sahakian, Alejandro Villagra, Asmita Mishra, Brian Betts, Mohamed Kharfan-Dabaja, Francisca Beato, Leonel Ochoa-Bayona, Joseph Pidala, Claudio Anasetti
Glucocorticoids for primary therapy of acute GVHD have limited responses. A phase I/II trial tested 4 weeks of deacetylase inhibitor panobinostat started within 48 h of glucocorticoids (1 mg/kg/day prednisone or equivalent) as primary treatment for patients with either classic acute GVHD (n = 16) or acute GVHD overlapping with chronic (n = 6). Four patients received 2.5 mg/m2 IV three times a week (TIW). Subsequent to discontinuation of IV panobinostat, patients received oral doses (PO). Two patients treated with 10 mg TIW (PO level 1) had progressive GVHD, after which patients were treated with 5 mg TIW (PO level -1; n = 16); 31/41 adverse events were possibly related, including thrombocytopenia (n = 13), leukopenia (n = 7), hypercholesterolemia (n = 3), hypertriglyceridemia (n = 5), anemia (n = 1), fatigue (n = 1), and hepatobiliary disorder (n = 1)...
April 18, 2018: Bone Marrow Transplantation
https://www.readbyqxmd.com/read/29669761/enhancer-remodeling-and-microrna-alterations-are-associated-with-acquired-resistance-to-alk-inhibitors
#7
Mi Ran Yun, Sun Min Lim, Seon-Kyu Kim, Hun Mi Choi, Kyoung Ho Pyo, Seong Keun Kim, Ji Min Lee, You Won Lee, Jae Woo Choi, Hye Ryun Kim, Min Hee Hong, Keeok Haam, Nanhyung Huh, Jong Hwan Kim, Yong Sung Kim, Hyo Sup Shim, Ross Andrew Soo, Jin-Yuan Shih, James Chih-Hsin Yang, Mirang Kim, Byoung Chul Cho
Anaplastic lymphoma kinase (ALK) inhibitors are highly effective in ALK fusion-positive lung cancer patients, but acquired resistance invariably emerges. Identification of secondary mutations has received considerable attention, but most cases cannot be explained by genetic causes alone, raising the possibility of epigenetic mechanisms in acquired drug resistance. Here we investigated the dynamic changes in the transcriptome and enhancer landscape during development of acquired resistance to ALK inhibitors...
April 18, 2018: Cancer Research
https://www.readbyqxmd.com/read/29656050/an-expanded-treatment-protocol-of-panobinostat-plus-bortezomib-and-dexamethasone-in-patients-with-previously-treated-myeloma
#8
Vincent L Hansen, Morton Coleman, Stephanie Elkins, Jeffrey P Letzer, Moshe Yair Levy, Lasika Seneviratne, Jessica Rine, Marina White, Emil T Kuriakose
BACKGROUND: Panobinostat was recently approved by the US Food and Drug Administration and European Commission in combination with bortezomib and dexamethasone for patients with multiple myeloma who have received ≥ 2 regimens, including bortezomib and an immunomodulatory drug. The PANEX (panobinostat expansion) treatment protocol provided access to panobinostat and gathered additional safety data before commercial availability. PATIENTS AND METHODS: In treatment phase 1, patients received panobinostat 20 mg 3 times per week plus bortezomib 1...
March 14, 2018: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/29624006/intrinsic-and-extrinsic-molecular-determinants-or-modulators-for-epigenetic-remodeling-and-reprogramming-of-somatic-cell-derived-genome-in-mammalian-nuclear-transferred-oocytes-and-resultant-embryos
#9
M Samiec, M Skrzyszowska
The efficiency of somatic cell cloning in mammals remains disappointingly low. Incomplete and aberrant reprogramming of epigenetic memory of somatic cell nuclei in preimplantation nuclear- transferred (NT) embryos is one of the most important factors that limit the cloning effectiveness. The extent of epigenetic genome-wide alterations, involving histone or DNA methylation and histone deacetylation, that are mediated by histone-lysine methyltransferases (HMTs) or DNA methyltransferases (DNMTs) and histone deacetylases (HDACs) can be modulated/reversed via exogenous inhibitors of these enzymes throughout in vitro culture of nuclear donor cells, nuclear recipient oocytes and/or cloned embryos...
March 2018: Polish Journal of Veterinary Sciences
https://www.readbyqxmd.com/read/29616865/single-agent-panobinostat-for-relapsed-refractory-diffuse-large-b-cell-lymphoma-clinical-outcome-and-correlation-with-genomic-data-a-phase-2-study-of-the-fondazione-italiana-linfomi
#10
Francesco Zaja, Flavia Salvi, Maura Rossi, Elena Sabattini, Andrea Evangelista, Giovannino Ciccone, Emanuele Angelucci, Gianluca Gaidano, Manuela Zanni, Marco Ladetto, Annalisa Chiappella, Umberto Vitolo, Pier Luigi Zinzani, Catello Califano, Alessandra Tucci, Caterina Patti, Stefano A Pileri, Valentina Lenti, Pier Paolo Piccaluga, Federica Cavallo, Stefano Volpetti, Giulia Perali, Sarit Assouline, Koren Kathleen Mann, Ryan Morin, Miguel Alcaide, Kevin Bushell, Renato Fanin, Alessandro Levis
We investigated panobinostat 40 mg three times weekly in 35 adult patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). Overall response rate and complete response were 17.1% and 11.4%, respectively. Median progression-free survival (PFS) and overall survival were 2.4 and 7.6 months, respectively. Calculated 12, 24 and 36 months PFS were 26%, 11% and 11%, respectively. Four patients who achieved a sustained CR, continued receiving panobinostat for an overall period of 44, 48, 50, 62 months...
April 4, 2018: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/29561759/epigenetic-modifications-in-thyroid-cancer-cells-restore-nis-and-radio-iodine-uptake-and-promote-cell-death
#11
Sabine Wächter, Alexander I Damanakis, Moritz Elxnat, Silvia Roth, Annette Wunderlich, Frederik A Verburg, Sebastian A Fellinger, Detlef K Bartsch, Pietro Di Fazio
Epigenetic modifications have been identified as being responsible for the de-differentiation of thyroid tissue and its malignant transformation. Cell proliferation inhibitory effects of the pan-deacetylase inhibitors panobinostat, SAHA and Trichostatin A (TSA), the modulation of the sodium iodide symporter (NIS; SLC5A5), thyroid transcription factor 1 (TTF1), high mobility group A2 (HMGA2), and H19 and their putative targeting miRNAs have been evaluated in vitro. The cell viability was measured in five thyroid cancer cell lines (FTC133, TPC1, BCPAP, 8505C, C643) by real time cell analyzer xCELLigence...
March 21, 2018: Journal of Clinical Medicine
https://www.readbyqxmd.com/read/29560114/deregulation-of-linc-pint-in-acute-lymphoblastic-leukemia-is-implicated-in-abnormal-proliferation-of-leukemic-cells
#12
Andoni Garitano-Trojaola, Edurne San José-Enériz, Teresa Ezponda, Juan Pablo Unfried, Arantxa Carrasco-León, Nerea Razquin, Marina Barriocanal, Amaia Vilas-Zornoza, Bruno Sangro, Victor Segura, Felipe Prósper, Puri Fortes, Xabier Agirre
Long Non-Coding RNAs (lncRNAs) are functional RNAs longer than 200 nucleotides in length. Several lncRNAs are involved in cell proliferation and are deregulated in several human tumors. Few lncRNAs have been described to play a role in Acute Lymphoblastic Leukemia (ALL). In this study, we carried out a genome wide lncRNA expression profiling in ALL samples and peripheral blood samples obtained from healthy donors. We detected 43 lncRNAs that were aberrantly expressed in ALL. Interestingly, among them, linc-PINT showed a significant downregulation in T and B-ALL...
February 27, 2018: Oncotarget
https://www.readbyqxmd.com/read/29522754/the-formation-of-giant-plasma-membrane-vesicles-enable-new-insights-into-the-regulation-of-cholesterol-efflux
#13
Alanna Sedgwick, M Olivia Balmert, Crislyn D'Souza-Schorey
Aberrant cellular cholesterol accumulation contributes to the pathophysiology of many diseases including neurodegenerative disorders such as Niemann-Pick Type C (NPC) and Alzheimer's Disease1-4 . Many aspects of cholesterol efflux from cells remain elusive. Here we describe the utility of cholesterol-rich giant plasma membrane vesicles (GPMVs) as a means to monitor cholesterol that is translocated to the plasma membrane for secretion. We demonstrate that small molecules known to enhance lipid efflux, including those in clinical trials for lipid storage disorders, enhance this GPMV formation...
April 15, 2018: Experimental Cell Research
https://www.readbyqxmd.com/read/29494986/low-expression-of-gfi-1-gene-is-associated-with-panobinostat-resistance-in-acute-myeloid-leukemia-through-influencing-the-level-of-ho-1
#14
Bingqing Cheng, Sishi Tang, Nana Zhe, Dan Ma, Kunlin Yu, Danna Wei, Zheng Zhou, Tingting Lu, Jishi Wang, Qin Fang
To improve the treatment outcomes of acute myeloid leukemia (AML), epigenetic modification has been widely tested and used in recent years. However, drug-resistance is still a choke point to cure the malignancy. The growth factor independent 1 transcriptional repressor (GFI-1), as a zinc-finger transcriptional repressor, can bind histone deacetylases to allow the transcriptional repression. According to the finding of our study, AML patients with low level of GFI-1 not only implicated poor prognosis but also caused Panobinostat-resistance...
April 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/29482060/inhibition-of-class-iia-histone-deacetylase-activity-by-gallic-acid-sulforaphane-tmp269-and-panobinostat
#15
Sin Young Choi, Hae Jin Kee, Li Jin, Yuhee Ryu, Simei Sun, Gwi Ran Kim, Myung Ho Jeong
Histone deacetylase (HDAC) inhibitors are gaining increasing attention as potential therapeutics for cardiovascular diseases as well as cancer. We recently reported that the class II HDAC inhibitor, MC1568, and the phytochemical, gallic acid, lowered high blood pressure in mouse models of hypertension. We hypothesized that class II HDACs may be involved in the regulation of hypertension. The aim of this study was to determine and compare the effects of well-known HDAC inhibitors (TMP269, panobinostat, and MC1568), phytochemicals (gallic acid, sulforaphane, and piceatannol), and anti-hypertensive drugs (losartan, carvedilol, and furosemide) on activities of class IIa HDACs (HDAC4, 5, 7, and 9)...
May 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/29468194/treatment-of-hiv-infected-individuals-with-the-histone-deacetylase-inhibitor-panobinostat-results-in-increased-numbers-of-regulatory-t-cells-and-limits-ex-vivo-lipopolysaccharide-induced-inflammatory-responses
#16
Christel Rothe Brinkmann, Jesper Falkesgaard Højen, Thomas Aagaard Rasmussen, Anne Sofie Kjær, Rikke Olesen, Paul W Denton, Lars Østergaard, Zhengyu Ouyang, Mathias Lichterfeld, Xu Yu, Ole Schmeltz Søgaard, Charles Dinarello, Martin Tolstrup
Histone deacetylase inhibitors (HDACi) modulate the transcriptional activity of all cells, including innate and adaptive immune cells. Therefore, we aimed to evaluate immunological effects of treatment with the HDACi panobinostat in HIV-infected patients during a clinical phase IIa latency reversal trial. Using flow cytometry, we investigated changes in T cell activation (CD69, CD38, HLA-DR) and the expression of CD39 and CTLA4 on regulatory T cells (Tregs). Whole-blood stimulations were performed and cytokine responses measured using Luminex...
January 2018: MSphere
https://www.readbyqxmd.com/read/29456798/-18-f-radiolabeled-panobinostat-allows-for-positron-emission-tomography-guided-delivery-of-a-histone-deacetylase-inhibitor
#17
Harikrishna Kommidi, Umberto Tosi, Uday B Maachani, Hua Guo, Christopher S Marnell, Benedict Law, Mark M Souweidane, Richard Ting
Histone deacetylase (HDAC) inhibition is becoming an increasingly popular approach to treat cancer, as HDAC overexpression is common in many malignancies. The blood-brain barrier (BBB) prevents systemically delivered drugs from reaching brain at effective concentration, making small-molecule-HDAC inhibition in brain tumors particularly challenging. To circumvent the BBB, novel routes for administering therapeutics are being considered in the clinic, and a need exists for drugs whose deliveries can be directly imaged, so that effective delivery across the BBB can be monitored...
February 8, 2018: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29445026/panobinostat-and-multiple-myeloma-in-2018
#18
Andrew J Yee, Noopur S Raje
No abstract text is available yet for this article.
February 14, 2018: Oncologist
https://www.readbyqxmd.com/read/29423093/combination-of-a-hypomethylating-agent-and-inhibitors-of-parp-and-hdac-traps-parp1-and-dnmt1-to-chromatin-acetylates-dna-repair-proteins-down-regulates-nurd-and-induces-apoptosis-in-human-leukemia-and-lymphoma-cells
#19
Benigno C Valdez, Yang Li, David Murray, Yan Liu, Yago Nieto, Richard E Champlin, Borje S Andersson
Combination of drugs that target different aspects of aberrant cellular processes is an efficacious treatment for hematological malignancies. Hypomethylating agents (HMAs) and inhibitors of poly(ADP-ribose) polymerases (PARPis) and histone deacetylases (HDACis) are clinically active anti-tumor drugs. We hypothesized that their combination would be synergistically cytotoxic to leukemia and lymphoma cells. Exposure of AML and lymphoma cell lines to the combination of the PARPi niraparib (Npb), the HMA decitabine (DAC) and the HDACi romidepsin (Rom) or panobinostat (Pano) synergistically inhibited cell proliferation by up to 70% via activation of the ATM pathway, increased production of reactive oxygen species, decreased mitochondrial membrane potential, and activated apoptosis...
January 9, 2018: Oncotarget
https://www.readbyqxmd.com/read/29396295/metabolomic-profiling-reveals-cellular-reprogramming-of-b-cell-lymphoma-by-a-lysine-deacetylase-inhibitor-through-the-choline-pathway
#20
Benet Pera, Jan Krumsiek, Sarit E Assouline, Rossella Marullo, Jayeshkumar Patel, Jude M Phillip, Lidia Román, Koren K Mann, Leandro Cerchietti
Despite the proven clinical antineoplastic activity of histone deacetylase inhibitors (HDACI), their effect has been reported to be lower than expected in B-cell lymphomas. Traditionally considered as "epigenetic drugs", HDACI modify the acetylation status of an extensive proteome, acting as general lysine deacetylase inhibitors (KDACI), and thus potentially impacting various branches of cellular metabolism. Here, we demonstrate through metabolomic profiling of patient plasma and cell lines that the KDACI panobinostat alters lipid metabolism and downstream survival signaling in diffuse large B-cell lymphomas (DLBCL)...
February 2018: EBioMedicine
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