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Ibrutinib

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https://www.readbyqxmd.com/read/28641630/-sdf-1%C3%AE-cxcr4-mediated-drug-resistance-can-be-reversed-by-ibrutinib-in-acute-lymphoblastic-leukemia
#1
Yuan-Yuan Hu, Shan-Dong Tao, Jing-Jing Ma, Li-Tao Zhou, Yue Chen, Liang Yu
OBJECTIVE: To explore the effect of Ibrutinib on the chemoresistance mediated by SDF-1α/CXCR4 axis in ALL cells. METHODS: Flow cytometry was used to detect the apoptosis of cell line and expression of surface membrane CXCR4, Western blot was used to determine the expression level of CXCR4, ERK and Bcl-xL proteins, qPCR was used to assay the mRNA level of CXCR4. RESULTS: Ibrutinib enhanced the apoptosis induced by adriamycin(ADR) (17.100±4...
June 2017: Zhongguo Shi Yan Xue Ye Xue za Zhi
https://www.readbyqxmd.com/read/28641100/bruton-s-tyrosine-kinase-btk-as-a-promising-target-in-solid-tumors
#2
REVIEW
J Molina-Cerrillo, T Alonso-Gordoa, P Gajate, E Grande
Bruton's tyrosine kinase (BTK) is a non-receptor intracellular kinase that belongs to the TEC-family tyrosine kinases together with bone marrow-expressed kinase (BMX), redundant-resting lymphocyte kinase (RLK), and IL-2 inducible T-Cell kinase (ITK). All these proteins play a key role in the intracellular signaling of both B and T lymphocytes. Recently, some preclinical data have demonstrated that BTK is present in certain tumor subtypes and in other relevant cells that are contributing to the tumor microenvironment such as dendritic cells, macrophages, myeloid derived suppressor cells and endothelial cells...
June 9, 2017: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/28629235/atrial-fibrillation-as-a-complication-of-ibrutinib-therapy-clinical-features-and-challenges-of-management
#3
Bronwyn C Thorp, Xavier Badoux
Ibrutinib is a Bruton's tyrosine kinase (BTK) inhibitor finding increasingly widespread use in non-Hodgkin lymphoma. Evidence of an increased risk of atrial fibrillation (AF) emerged in Phase III studies with a median incidence of approximately 6%. The mechanism remains unknown, but inhibition of a cardioprotective pathway has been proposed. Ibrutinib induces a platelet function defect, increasing the bleeding risk of anticoagulation for AF stroke prophylaxis. Multiple potential drug interactions are an added complication...
June 20, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28627951/the-safety-of-bruton-s-tyrosine-kinase-inhibitors-for-the-treatment-of-chronic-lymphocytic-leukemia
#4
Phu N Tran, Susan O'Brien
The approval of ibrutinib has revolutionized the therapeutic landscape of chronic lymphocytic leukemia (CLL). Currently ibrutinib is indicated for patients that are both treatment naïve as well as those with relapsed CLL. Ibrutinib is generally well-tolerated with durable responses that improve over time in most patients. Important toxicities include atrial fibrillation and bleeding. Areas Cover: This review covers the pharmacokinetics, pharmacodynamics, safety and efficacy of ibrutinib in the treatment of CLL...
June 19, 2017: Expert Opinion on Drug Safety
https://www.readbyqxmd.com/read/28619981/ibrutinib-unmasks-critical-role-of-bruton-tyrosine-kinase-in-primary-cns-lymphoma
#5
Christian Grommes, Alessandro Pastore, Nicolaos Palaskas, Sarah S Tang, Carl Campos, Derrek Schartz, Paolo Codega, Donna Nichol, Owen Clark, Wan-Ying Hsieh, Daniel Rohle, Marc K Rosenblum, Agnes Viale, Viviane Tabar, Cameron W Brennan, Igor T Gavrilovic, Thomas J Kaley, Craig Nolan, Antonio M P Omuro, Elena Pentsova, Alissa A Thomas, Elina Tsyvkin, Ariela Noy, M Lia Palomba, Paul A Hamlin, Craig Sauter, Craig H Moskowitz, Julia Wolfe, Ahmet Dogan, Minhee Won, Jon Glass, Scott Peak, Enrico C Lallana, Vaios Hatzoglou, Anne S Reiner, Philip Gutin, Jason T Huse, Katherine Panageas, Thomas G Graeber, Nikolaus Schultz, Lisa M DeAngelis, Ingo K Mellinghoff
Bruton tyrosine kinase (BTK) links the B-cell antigen receptor (BCR) and Toll-like receptors with Nuclear factor kappa B (NF-κB). The role of BTK in primary CNS lymphoma (PCNSL) is unknown. We performed a Phase 1 clinical trial with ibrutinib, the first-in-class BTK inhibitor, for patients with relapsed or refractory CNS Lymphoma. Clinical responses to ibrutinib occurred in 10/13 (77%) PCNSL patients, including five complete responses. The only PCNSL with complete ibrutinib resistance harbored a mutation within the coiled-coil domain of Caspase Recruitment Domain Family Member 11, a known ibrutinib resistance mechanism...
June 15, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28619845/the-prohibitin-binding-compound-fluorizoline-induces-apoptosis-in-chronic-lymphocytic-leukemia-cells-through-the-upregulation-of-noxa-and-synergizes-with-ibrutinib-aicar-or-venetoclax
#6
Ana M Cosialls, Helena Pomares, Daniel Iglesias-Serret, José Saura-Esteller, Sonia Núñez-Vázquez, Diana M González-Gironès, Esmeralda de la Banda, Sara Preciado, Fernando Albericio, Rodolfo Lavilla, Gabriel Pons, Eva M González-Barca, Joan Gil
Fluorizoline is a new synthetic molecule that induces apoptosis by selectively targeting prohibitins. In this study, the pro-apoptotic effect of fluorizoline was assessed in 34 primary samples from patients with chronic lymphocytic leukemia. Fluorizoline induced apoptosis in chronic lymphocytic leukemia cells at concentrations in the low micromolar range. All primary samples were sensitive to fluorizoline irrespectively of patients' clinical or genetic features, whereas normal T lymphocytes were less sensitive...
June 15, 2017: Haematologica
https://www.readbyqxmd.com/read/28617062/novel-approaches-to-targeting-myd88-in-waldenstr%C3%A3-m-macroglobulinemia
#7
Jorge J Castillo, Zachary R Hunter, Guang Yang, Steven P Treon
Waldenström macroglobulinemia (WM) is an incurable lymphoma characterized by the accumulation of IgM-producing lymphoplasmacytic cells in the bone marrow and other organs. Although WM patients can experience prolonged remissions, the disease invariably recurs advocating for the need of novel treatments in order to achieve higher response and survival rates. The discovery of a recurrent mutation in the MYD88 gene and an increased understanding behind the biology of MYD88 signaling have provided the opportunity to developing novel agents targeting the MYD88 pathway...
June 15, 2017: Expert Review of Hematology
https://www.readbyqxmd.com/read/28615655/secreted-igm-deficiency-leads-to-increased-bcr-signaling-that-results-in-abnormal-splenic-b-cell-development
#8
Dimitrios Tsiantoulas, Mate Kiss, Barbara Bartolini-Gritti, Andreas Bergthaler, Ziad Mallat, Hassan Jumaa, Christoph J Binder
Mice lacking secreted IgM (sIgM (-/-)) antibodies display abnormal splenic B cell development, which results in increased marginal zone and decreased follicular B cell numbers. However, the mechanism by which sIgM exhibit this effect is unknown. Here, we demonstrate that B cells in sIgM (-/-) mice display increased B cell receptor (BCR) signaling as judged by increased levels of phosphorylated Bruton's tyrosine kinase (pBtk), phosphorylated Spleen tyrosine kinase (pSyk), and nuclear receptor Nur77. Low dosage treatment with the pBtk inhibitor Ibrutinib reversed the altered B cell development in the spleen of sIgM (-/-) mice, suggesting that sIgM regulate splenic B cell differentiation by decreasing BCR signaling...
June 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28615297/disruption-of-aneuploidy-and-senescence-induced-by-aurora-inhibition-promotes-intrinsic-apoptosis-in-double-hit-or-double-expressor-diffuse-large-b-cell-lymphomas
#9
Daruka Mahadevan, Shariful Islam, Wenqing Qi, Carla Morales, Laurence Cooke, Catherine Spier, Eric Weterings
Double Hit (DH) or Double Expressor (DE) diffuse large B-cell lymphoma (DLBCL) are aggressive Non-Hodgkin's Lymphomas (NHLs) with translocations and/or over-expressions of MYC and BCL-2, that are difficult to treat. Aurora kinase (AK) inhibition with alisertib in DH/DE-DLBCL induces cell death in ~30%, while ~70% are aneuploid and senescent cells (AASCs), a mitotic escape mechanism contributing to drug resistance. These AASCs elaborated a high metabolic rate by increased AKT/mTOR and ERK/MAPK activity via BTK signaling through the chronic active B-cell receptor (BCR) pathway...
June 14, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28614781/cell-lines-generated-from-a-chronic-lymphocytic-leukemia-mouse-model-exhibit-constitutive-btk-and-akt-signaling
#10
Simar Pal Singh, Saravanan Y Pillai, Marjolein J W de Bruijn, Ralph Stadhouders, Odilia B J Corneth, Henk Jan van den Ham, Alice Muggen, Wilfred van IJcken, Erik Slinger, Annemieke Kuil, Marcel Spaargaren, Arnon P Kater, Anton W Langerak, Rudi W Hendriks
Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of mature CD5+ B cells in blood. Spontaneous apoptosis of CLL cells in vitro has hampered in-depth investigation of CLL pathogenesis. Here we describe the generation of three monoclonal mouse cell lines, EMC2, EMC4 and EMC6, from the IgH.TEμ CLL mouse model based on sporadic expression of SV40 large T antigen. The cell lines exhibit a stable CD5+CD43+IgM+CD19+ CLL phenotype in culture and can be adoptively transferred into Rag1-/- mice...
May 26, 2017: Oncotarget
https://www.readbyqxmd.com/read/28613814/2-chloropropionamide-as-a-low-reactivity-electrophile-for-irreversible-small-molecule-probe-identification
#11
Dharmaraja Allimuthu, Drew J Adams
Resurgent interest in covalent target engagement in drug discovery has demonstrated that small molecules containing weakly reactive electrophiles can be safe and effective therapies. Several recently FDA-approved drugs feature an acrylamide functionality to selectively engage cysteine side chains of kinases (Ibrutinib, Afatinib, and Neratinib). Additional electrophilic functionalities whose reactivity is compatible with highly selective target engagement and in vivo application could open new avenues in covalent small molecule discovery...
June 14, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28605616/managing-patients-with-tp53-deficient-chronic-lymphocytic-leukemia
#12
Jennifer Edelmann, John G Gribben
Patients with chronic lymphocytic leukemia (CLL) having a chromosomal loss on the short arm of chromosome 17 including the TP53 gene locus (17p deletion) and/or having mutations in TP53 have a short overall survival and, until recently, limited treatment options. The recent introduction of two novel substance classes, B-cell receptor inhibitors and BH3 mimetics, into CLL treatment has provided enormous clinical progress in this previously difficult-to-treat patient subgroup characterized by high risk for treatment failure with standard chemoimmunotherapy and rapid disease progression...
June 2017: Journal of Oncology Practice
https://www.readbyqxmd.com/read/28596280/extracellular-vesicles-of-bone-marrow-stromal-cells-rescue-chronic-lymphocytic-leukemia-b-cells-from-apoptosis-enhance-their-migration-and-induce-gene-expression-modifications
#13
Emerence Crompot, Michael Van Damme, Karlien Pieters, Marjorie Vermeersch, David Perez-Morga, Philippe Mineur, Marie Maerevoet, Nathalie Meuleman, Dominique Bron, Laurence Lagneaux, Basile Stamatopoulos
Interactions between chronic lymphocytic leukemia B-cells and the bone marrow microenvironment play a major function in the physiopathology of chronic lymphocytic leukemia. Extracellular vesicles, which are composed of exosomes and microparticles, play an important role in cell communication. However, little is known about their role in chronic lymphocytic leukemia/microenvironment interactions. In the present study, extracellular vesicles purified by ultracentrifugation from bone marrow mesenchymal stromal cell cultures were added to chronic lymphocytic leukemia B-cells...
June 8, 2017: Haematologica
https://www.readbyqxmd.com/read/28592889/extended-follow-up-and-impact-of-high-risk-prognostic-factors-from-the-phase-3-resonate-tm-study-in-patients-with-previously-treated-cll-sll
#14
J R Brown, P Hillmen, S O'Brien, J C Barrientos, N M Reddy, S E Coutre, C S Tam, S P Mulligan, U Jaeger, P M Barr, R R Furman, T J Kipps, F Cymbalista, P Thornton, F Caligaris-Cappio, J Delgado, M Montillo, S DeVos, C Moreno, J M Pagel, T Munir, J A Burger, D Chung, J Lin, L Gau, B Chang, G Cole, E Hsu, D F James, J C Byrd
In the phase 3 RESONATE(TM) study, ibrutinib demonstrated superior progression-free survival (PFS), overall survival (OS), and overall response rate (ORR) compared with ofatumumab in relapsed/refractory CLL patients with high-risk prognostic factors. We report updated results from RESONATE in these traditionally chemotherapy resistant high-risk genomic subgroups at a median follow-up of 19 months. Mutations were detected by Foundation One Heme Panel. Baseline mutations in the ibrutinib arm included TP53 (51%), SF3B1 (31%), NOTCH1 (28%), ATM (19%), and BIRC3 (14%)...
June 8, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28592763/malignant-lymphoma-pathophysiology-and-current-therapy
#15
Koji Izutsu
Recent advances in the understanding of molecular pathogenesis of lymphoma have enabled us to clearly define disease entity by means of a disease-specific gene mutation and to select candidates for novel targeted therapy. In this review three different clinically relevant topics related to the molecular pathogenesis of lymphoma were covered. In the 2016 revision of the World Health Organization classification of lymphoid malignancies, firstly, disease-specific mutations such as MYD88 L265P in Waldenström macroglobulinemia and BRAF V600E in hairy cell leukemia were incorporated into diagnostic tests, and secondly, the determination of cell-of-origin in diffuse large B-cell lymphoma (DLBCL) was strongly recommended in diagnosis...
2017: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/28592762/chronic-lymphocytic-leukemia-pathophysiology-and-current-therapy
#16
Jun Takizawa
Chronic lymphocytic leukemia (CLL) is the most frequent adult leukemia in western countries, but it is rare in Japan. Several mutations have been identified in patients with CLL using next-generation sequencing, but disease-specific mutations were not found. Some mutations, such as those in TP53, NOTCH1, SF3B, and BIRC3 are useful for risk stratification and prognosis prediction in patients with CLL. Strategies for treating CLL are rapidly evolving, with targeted agents such as the B-cell receptor signaling pathway inhibitors (ibrutinib, idelalisib), novel anti-CD20 monoclonal antibody (obinutuzumab), and Bcl-2 inhibitor (venetoclax) being approved by the US Food and Drug Administration...
2017: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/28592170/current-options-to-manage-waldenstr%C3%A3-m-s-macroglobulinemia
#17
Giulia Benevolo, Maura Nicolosi, Elisa Santambrogio, Umberto Vitolo
Waldenström's macroglobulinemia (WM) is a rare, incurable B-cell lymphoma, with a median survival of 5-10 years in symptomatic patients. There is no consensus on the standard of care and several agents are currently used in these patients. Areas covered: In this article, we will review the use of standard therapies and new drugs investigated such as monoclonal antibodies, proteasome inhibitors, immunomodulatory agents, Bruton's tyrosine kinase inhibitors and novel agents in early-stage development. Expert commentary: RCD (Rituximab/Cyclophosphamide/Dexamethasone) is an effective and safe treatment in first line in WM...
June 19, 2017: Expert Review of Hematology
https://www.readbyqxmd.com/read/28588835/concomitant-imatinib-and-ibrutinib-in-a-patient-with-chronic-myelogenous-leukemia-and-chronic-lymphocytic-leukemia
#18
Lauren K Shea, Fady M Mikhail, Andres Forero-Torres, Randall S Davis
The availability of kinase and other small-molecule inhibitors to treat hematologic malignancies is increasing. Accordingly, novel regimens that employ these therapeutics are rapidly evolving. Herein we report the safe and effective administration of two targeted kinase inhibitors in a patient with concomitant chronic myelogenous leukemia and chronic lymphocytic leukemia.
June 2017: Clinical Case Reports
https://www.readbyqxmd.com/read/28588800/ibrutinib-induced-severe-liver-injury
#19
Amara G Nandikolla, Olga Derman, Deborah Nautsch, Qiang Liu, Hatef Massoumi, Sangeetha Venugopal, Ira Braunschweig, Murali Janakiram
Ibrutinib, an inhibitor of the Bruton's tyrosine kinase of the B-cell receptor pathway, is an effective therapeutic agent for B-cell lymphomas. As these drugs are novel, long-term or rare adverse events are not yet known. We report the first case of ibrutinib-induced severe liver injury in a patient with relapsed/refractory CLL.
June 2017: Clinical Case Reports
https://www.readbyqxmd.com/read/28573668/establishing-a-chemical-genetic-link-between-bruton-tyrosine-kinase-activity-in-malignant-b-cells-and-cell-functions-involved-in-the-micro-environmental-dialogue
#20
Elisa Göckeritz, Verena Vondey, Anna Guastafierro, Maja Pizevska, Floyd Hassenrück, Lars Neumann, Michael Hallek, Günter Krause
To elucidate their mechanism of action, inhibitors of Bruton tyrosine kinase (BTK) and resistant BTK mutants were employed to dissect target-dependent cellular functions. BTK-C481S and -T474I, expressed in Ramos and NALM-6 cells, maintained BTK auto-phosphorylation under treatment with ibrutinib or dasatinib, respectively, which showed only modest cytotoxicity. Retained activity of BTK-T474 partially rescued cell migration from inhibition by dasatinib. Importantly, resistant BTK mutants reconstituted B cell receptor-triggered chemokine secretion in the presence of corresponding inhibitors, demonstrating that BTK activity is connected with cell-intrinsic functions of malignant B cells with importance for their dialogue with the micro-environment...
June 1, 2017: British Journal of Haematology
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