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Panobinostat

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https://www.readbyqxmd.com/read/28622959/a-phase-i-ii-trial-of-panobinostat-in-combination-with-lenalidomide-in-patients-with-relapsed-or-refractory-hodgkin-lymphoma
#1
Joseph J Maly, Beth A Christian, Xiaohua Zhu, Lai Wei, Jennifer L Sexton, Samantha M Jaglowski, Steven M Devine, Todd A Fehniger, Nina D Wagner-Johnston, Mitch A Phelps, Nancy L Bartlett, Kristie A Blum
BACKGROUND: Lenalidomide and panobinostat have shown single-agent efficacy of 14% to 50% and 27% to 58%, respectively, in Hodgkin lymphoma (HL). This phase I/II study was conducted to determine the maximum tolerated dose (MTD), safety, and efficacy of lenalidomide combined with panobinostat in relapsed/refractory HL. PATIENTS AND METHODS: In the phase I trial, previously treated patients with classical or lymphocyte-predominant HL received escalating doses of lenalidomide on days 1 to 21 and panobinostat 3 times a week (TIW) every 28 days...
June 2017: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/28601492/new-agents-in-multiple-myeloma-an%C3%A2-examination-of-safety-profiles
#2
REVIEW
Sara Bringhen, Edwin De Wit, Meletios-Athanassios Dimopoulos
Numerous treatments are available for relapsed and/or refractory multiple myeloma (MM), with safety profiles varying across drug classes and across agents within the same class. Thus, it is important to understand the toxicities of each antimyeloma agent when making treatment decisions. Neutropenia is commonly associated with lenalidomide and pomalidomide, and may be common with histone deacetylase (HDAC) inhibitors, but is relatively unusual with thalidomide, bortezomib, and carfilzomib. Infection was common in trials of lenalidomide and pomalidomide, and upper respiratory tract infection and pneumonia have been seen with carfilzomib...
May 10, 2017: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/28599306/panobinostat-a-histone-deacetylase-inhibitor-suppresses-leptomeningeal-seeding-in-a-medulloblastoma-animal-model
#3
Ji Hoon Phi, Seung Ah Choi, Pil Ae Kwak, Ji Yeoun Lee, Kyu-Chang Wang, Do Won Hwang, Seung-Ki Kim
Leptomeningeal seeding is a strong negative prognostic factor for medulloblastoma (MB). The mechanism of leptomeningeal seeding is unclear but may involve epigenetic regulation. In this study, we evaluated the feasibility of a histone deacetylase (HDAC) inhibitor, panobinostat, in the suppression of MB leptomeningeal seeding.Panobinostat decreased the cell viability and proliferation, inducing cell cycle arrest and apoptosis in MB cell lines. The migration and adhesion capabilities were significantly decreased...
May 24, 2017: Oncotarget
https://www.readbyqxmd.com/read/28560392/the-blueberry-component-pterostilbene-has-potent-anti-myeloma-activity-in-bortezomib-resistant-cells
#4
Gege Chen, Zhijian Xu, Gaomei Chang, Jun Hou, Liangning Hu, Yiwen Zhang, Dandan Yu, Bo Li, Shuaikang Chang, Yongsheng Xie, Yong Zhang, Rong Wei, Huiqun Wu, Wenqin Xiao, Xi Sun, Yi Tao, Lu Gao, Bojie Dai, Jumei Shi, Weiliang Zhu
Multiple myeloma (MM) is an incurable hematologic malignancy because of its drug resistance. Pterostilbene (Pter) is found mainly in blueberries and grapes. The effects of Pter and its exact pharmacologic mechanisms on chemoresistant myeloma are not known. Herein, we investigated the anti-myeloma activity of Pter in bortezomib-resistant cell line H929R and explored the related mechanism of action for the first time. We found that Pter inhibited proliferation of H929R cells and promoted apoptosis of the cells through a caspase-dependent pathway, loss of mitochondrial membrane potential, and activation of Akt and p38 mitogen-activated protein kinase (MAPK) signaling pathways...
May 30, 2017: Oncology Reports
https://www.readbyqxmd.com/read/28556890/recent-progress-in-relapsed-multiple-myeloma-therapy-implications-for-treatment-decisions
#5
REVIEW
Philippe Moreau, Edwin de Wit
The availability of novel therapies for the treatment of multiple myeloma has had a dramatic impact on the depth of response that can be expected on initial treatment. Despite these advances, disease relapse remains inevitable in most patients and brings with it a different set of priorities for therapy. The most recent wave of novel agents may have a particular impact in the relapsed setting. In this review, we examine the evidence currently available from clinical trials for the use of novel agents, particularly in the formation of triplet therapy...
May 30, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28546581/a-phase-1b-2b-multicenter-study-of-oral-panobinostat-plus-azacitidine-in-adults-with-mds-cmml-or-aml-with-%C3%A2-30-blasts
#6
G Garcia-Manero, M A Sekeres, M Egyed, M Breccia, C Graux, J D Cavenagh, H Salman, A Illes, P Fenaux, D J DeAngelo, R Stauder, K Yee, N Zhu, J-H Lee, D Valcarcel, A MacWhannell, Z Borbenyi, L Gazi, S Acharyya, S Ide, M Marker, O G Ottmann
Treatment with azacitidine (AZA), a demethylating agent, prolonged overall survival (OS) vs conventional care in patients with higher-risk myelodysplastic syndromes (MDS). As median survival with monotherapy is <2 years, novel agents are needed to improve outcomes. This phase 1b/2b trial (n=113) was designed to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of panobinostat (PAN) + AZA (phase 1b) and evaluate early efficacy and safety of PAN+AZA vs AZA monotherapy (phase 2b) in patients with higher-risk MDS, chronic myelomonocytic leukemia, or oligoblastic acute myeloid leukemia with <30% blasts...
May 26, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28539449/anti-hiv-1-adcc-antibodies-following-latency-reversal-and-treatment-interruption
#7
Wen Shi Lee, Anne B Kristensen, Thomas A Rasmussen, Martin Tolstrup, Lars Østergaard, Ole S Søgaard, Bruce D Wines, P Mark Hogarth, Arnold Reynaldi, Miles P Davenport, Sean Emery, Janaki Amin, David A Cooper, Virginia L Kan, Julie Fox, Henning Gruell, Matthew S Parsons, Stephen J Kent
There is growing interest in utilizing antibody-dependent cellular cytotoxicity (ADCC) to eliminate infected cells following reactivation from HIV-1 latency. A potential barrier is that HIV-1-specific ADCC antibodies decline in patients on long-term antiretroviral therapy (ART) and may not be sufficient to eliminate reactivated latently infected cells. It is not known whether reactivation from latency with latency-reversing agents (LRA) could provide sufficient antigenic stimulus to boost HIV-1-specific ADCC...
May 24, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28516379/panobinostat-enhances-growth-suppressive-effects-of-progestin-on-endometrial-carcinoma-by-increasing-progesterone-receptor-and-mitogen-inducible-gene-6
#8
Hirofumi Ando, Tsutomu Miyamoto, Hiroyasu Kashima, Shotaro Higuchi, Koichi Ida, David Hamisi Mvunta, Tanri Shiozawa
Although progestin has been used to treat endometrial hyperplasia and endometrial carcinoma (EC), its therapeutic efficacy is limited. In order to improve this, the underlining mechanisms of the effects of progestin need to be elucidated in more detail. In the present study, we examined the involvement of mitogen-inducible gene-6 (MIG6), a negative regulator of the EGF receptor, in the progestin-mediated growth suppression of endometrial epithelia. The immunohistochemical expression of MIG6 was elevated in the early to mid-secretory phases of normal endometrium and also with endometrial hyperplasia after medroxyprogesterone acetate (MPA) therapy...
May 17, 2017: Hormones & Cancer
https://www.readbyqxmd.com/read/28507307/a-novel-indication-for-panobinostat-as-a-senolytic-drug-in-nsclc-and-hnscc
#9
Leleesha Samaraweera, Alfred Adomako, Alicia Rodriguez-Gabin, Hayley M McDaid
Panobinostat (pano) is an FDA-approved histone deacetylase inhibitor. There is interest in evaluating alternate dosing schedules and novel combinations of pano for the treatment of upper aerodigestive and lung malignancies; thus we evaluated it in combination with Taxol, a chemotherapeutic with activity in both diseases. Dose-dependent synergy was observed in Non-Small Cell Lung Cancer (NSCLC) and Head and Neck Squamous Cell Carcinoma (HNSCC) cell lines and was due to senescence rather than potentiation of cell death...
May 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28505595/epigenetic-drug-combination-induces-remission-in-mouse-xenograft-models-of-pediatric-acute-myeloid-leukemia
#10
Anilkumar Gopalakrishnapillai, E Anders Kolb, Suzanne M McCahan, Sonali P Barwe
Aberrations in epigenetic modifications contribute to leukemogenesis in childhood acute myeloid leukemia (AML). We combined DNA hypomethylating agent azacitidine with histone deacetylase inhibitor panobinostat in preclinical models of childhood AML. Synergistic cytotoxic effect upon treatment with azacitidine and panobinostat with combination indices <1.0 was observed. Azacitidine and panobinostat increased median survival by 26 and 6days respectively in MV4;11 xenografted mice. Mice treated with both drugs showed a drastic reduction in leukemic burden leading to complete remission sustained for the duration of the experimental period lasting more than 519days...
July 2017: Leukemia Research
https://www.readbyqxmd.com/read/28482026/pre-clinical-drug-screen-reveals-topotecan-actinomycin-d-and-volasertib-as-potential-new-therapeutic-candidates-for-etmr-brain-tumor-patients
#11
Christin Schmidt, Nil A Schubert, Sebastian Brabetz, Norman Mack, Benjamin Schwalm, Jennifer A Chan, Florian Selt, Christel Herold-Mende, Olaf Witt, Till Milde, Stefan M Pfister, Andrey Korshunov, Marcel Kool
Background: Embryonal tumor with multilayered rosettes (ETMR) is a rare and aggressive embryonal brain tumor that solely occurs in infants and young children and has only recently been recognized as a separate brain tumor entity in the WHO classification for CNS tumors. Patients have a very dismal prognosis with a median survival of 12 months upon diagnosis despite aggressive treatment. The aim of this study was to develop novel treatment regimens in a pre-clinical drug screen in order to inform potentially more active clinical trial protocols...
May 8, 2017: Neuro-oncology
https://www.readbyqxmd.com/read/28476749/panobinostat-induces-cd38-upregulation-and-augments-the-anti-myeloma-efficacy-of-daratumumab
#12
Estefanía García-Guerrero, Tea Gogishvili, Sophia Danhof, Martin Schreder, Celine Pallaud, Jose Antonio Pérez-Simón, Hermann Einsele, Michael Hudecek
No abstract text is available yet for this article.
May 5, 2017: Blood
https://www.readbyqxmd.com/read/28415789/hmga2-translocation-induced-in-skin-tumorigenesis
#13
Yong Li, Xiang-Ying Pi, Kelsey Boland, Sonali Lad, Kelly Johnson, Catherine Verfaillie, Rebecca J Morris
Hmga2 protein, a transcription factor involved in chromatin architecture, is expressed chiefly during development, where it has many key biological functions. When expressed in adult tissues from in various organs, Hmga2 is always related to cancer development. The role of Hmga2 in skin tumorigenesis is, however, not yet understood. We demonstrated that Hmga2 can be found in non-transformed epidermis, specifically located to the membrane of keratinocytes (KCs) in epidermis. Ex vivo culture of KCs and development of skin carcinomas in DMBA and TPA mouse models was associated with translocation of the Hmga2 protein from the membrane into the nucleus, where Hmga2 induced its own expression by binding to the Hmga2 promoter...
May 2, 2017: Oncotarget
https://www.readbyqxmd.com/read/28398261/novel-proteasome-inhibitors-and-histone-deacetylase-inhibitors-progress-in-myeloma-therapeutics
#14
REVIEW
Saurabh Chhabra
The unfolded protein response is responsible for the detection of misfolded proteins and the coordination of their disposal and is necessary to maintain the cellular homoeostasis. Multiple myeloma cells secrete large amounts of immunoglobulins, proteins that need to be correctly folded by the chaperone system. If this process fails, the misfolded proteins have to be eliminated by the two main garbage-disposal systems of the cell: proteasome and aggresome. The blockade of either of these systems will result in accumulation of immunoglobulins and other toxic proteins in the cytoplasm and cell death...
April 11, 2017: Pharmaceuticals
https://www.readbyqxmd.com/read/28388244/which-therapies-will-move-to-the-front-line-for-multiple-myeloma
#15
REVIEW
María J Cejalvo, Javier de la Rubia
Despite substantial progress, multiple myeloma (MM) remains an incurable disease. Recently the availability of several novel drugs with different and innovative mechanisms of action (daratumumab, elotuzumab, carfilzomib, ixazomib, and panobinostat) has increased the therapeutic options but has also increased complexity in the management of patients with MM. Areas covered: The outstanding results observed in the relapsed setting with regimens including these new drugs has provided the investigators with several treatment options that are being tested also in patients with newly diagnosed MM...
May 2017: Expert Review of Hematology
https://www.readbyqxmd.com/read/28363998/e3-ligase-ciap2-mediates-downregulation-of-mre11-and-radiosensitization-in-response-to-hdac-inhibition-in-bladder-cancer
#16
Judith Nicholson, Sarah J Jevons, Blaz Groselj, Sophie Ellermann, Rebecca Konietzny, Martin Kerr, Benedikt M Kessler, Anne E Kiltie
The MRE11/RAD50/NBS1 (MRN) complex mediates DNA repair pathways, including double-strand breaks induced by radiotherapy. Meiotic recombination 11 homolog (MRE11) is downregulated by histone deacetylase inhibition (HDACi), resulting in reduced levels of DNA repair in bladder cancer cells and radiosensitization. In this study, we show that the mechanism of this downregulation is posttranslational and identify a C-terminally truncated MRE11, which is formed after HDAC inhibition as full-length MRE11 is downregulated...
March 31, 2017: Cancer Research
https://www.readbyqxmd.com/read/28353192/three-cases-of-relapsed-refractory-multiple-myeloma-under-hemodialysis-treated-with-panobinostat-bortezomib-dexamethasone-fvd
#17
Yasunobu Sekiguchi, Haruko Takizawa, Tadaaki Inano, Yasutaka Fukuda, Mutsumi Wakabayashi, Keiji Sugimoto, Shigeki Tomita, Hiroshi Izumi, Noriko Nakamura, Tomohiro Sawada, Yasunori Ohta, Norio Komatsu, Masaaki Noguchi
Three patients under hemodialysis (HD) with relapsed/refractory multiple myeloma (MM) were administered panobinostat/bortezomib/dexamethasone (FVD). Case 1: The patient was a 66-year-old male with BJP-κ. FVD was effective, but HD could not be discontinued. He developed Grade 3 adverse events (AEs), including nausea, dehydration, and fatigue, following the common terminology criteria for adverse events v4.0. FVD was discontinued after the third course, while HD was continued. Case 2: The patient was a 65-year-old female with IgG-λ + BJP-λ...
March 28, 2017: International Journal of Hematology
https://www.readbyqxmd.com/read/28352655/panobinostat-acts-synergistically-with-ibrutinib-in-diffuse-large-b-cell-lymphoma-cells-with-myd88-l265-mutations
#18
Patrizia Mondello, Elliott J Brea, Elisa De Stanchina, Eneda Toska, Aaron Y Chang, Myles Fennell, Venkatraman Seshan, Ralph Garippa, David A Scheinberg, José Baselga, Hans-Guido Wendel, Anas Younes
Diffuse large B cell lymphoma (DLBCL) frequently harbors genetic alterations that activate the B cell receptor (BCR) and TLR pathways, which converge to activate NF-κB. While selective inhibition of BTK with ibrutinib causes clinical responses in relapsed DLBCL patients, most responses are partial and of a short duration. Here, we demonstrated that MyD88 silencing enhanced ibrutinib efficacy in DLBCL cells harboring MyD88 L265P mutations. Chemical downregulation of MyD88 expression with HDAC inhibitors also synergized with ibrutinib...
March 23, 2017: JCI Insight
https://www.readbyqxmd.com/read/28347676/treating-multiple-myeloma-patients-with-oral-therapies
#19
REVIEW
Shaji K Kumar, Ravi Vij, Stephen J Noga, Deborah Berg, Lonnie Brent, Lawrence Dollar, Ajai Chari
Recent advances have highlighted the importance of long-term, continuous treatment in multiple myeloma (MM) to improve survival. However, treatment burden continues to negatively impact the real-world duration of MM therapy, and strategies to limit the adverse impact of treatment on patient quality of life are therefore particularly important. Oral MM therapies include the immunomodulatory drugs lenalidomide, thalidomide, and pomalidomide; the alkylating agents melphalan and cyclophosphamide; the histone deacetylase inhibitor panobinostat; the corticosteroids prednisone and dexamethasone; and the proteasome inhibitor ixazomib...
May 2017: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/28338993/dihydrocelastrol-inhibits-multiple-myeloma-cell-proliferation-and-promotes-apoptosis-through-erk1-2-and-il-6-stat3-pathways-in-vitro-and-in-vivo
#20
Liangning Hu, Huiqun Wu, Bo Li, Dongliang Song, Guang Yang, Gege Chen, Bingqian Xie, Zhijian Xu, Yong Zhang, Dandan Yu, Jun Hou, Wenqin Xiao, Xi Sun, Gaomei Chang, Yiwen Zhang, Lu Gao, Bojie Dai, Yi Tao, Jumei Shi, Weiliang Zhu
Multiple myeloma (MM) is the second most frequent malignant hematological disease. Dihydrocelastrol (DHCE) is synthesized by hydrogenated celastrol, a treterpene isolated from Chinese medicinal plant Tripterygium regelii. In this study, we first reported the anti-tumor activity of DHCE on MM cells. We found that DHCE could inhibit cell proliferation and promote apoptosis through caspase-dependent way in vitro. In addition, DHCE could inactivate the expression of interleukin (IL)-6 and downregulate the phosphorylation of extracellular regulated protein kinases (ERK1/2) and the signal transducer and activator of transcription 3 (STAT3) in MM...
May 1, 2017: Acta Biochimica et Biophysica Sinica
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