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Robert Campbell, Geoffrey Chong, Eliza A Hawkes
Bruton's tyrosine kinase (BTK) is a critical terminal enzyme in the B-cell antigen receptor (BCR) pathway. BTK activation has been implicated in the pathogenesis of certain B-cell malignancies. Targeting this pathway has emerged as a novel target in B-cell malignancies, of which ibrutinib is the first-in-class agent. A few other BTK inhibitors (BTKi) are also under development (e.g., acalabrutinib). While the predominant action of BTKi is the blockade of B-cell receptor pathway within malignant B-cells, increasing the knowledge of off-target effects as well as a potential role for B-cells in proliferation of solid malignancies is expanding the indication of BTKi into non-hematological malignancies...
March 21, 2018: Journal of Clinical Medicine
John C Byrd, Stephen Smith, Nina Wagner-Johnston, Jeff Sharman, Andy I Chen, Ranjana Advani, Bradley Augustson, Paula Marlton, S Renee Commerford, Kwame Okrah, Lichuan Liu, Elaine Murray, Elicia Penuel, Ashley F Ward, Ian W Flinn
GDC-0853 is a selective, reversible, and non-covalent inhibitor of Bruton's tyrosine kinase (BTK) that does not require interaction with the Cys481 residue for activity. In this first-in-human phase 1 study we evaluated safety, tolerability, pharmacokinetics, and activity of GDC-0853 in patients with relapsed or refractory non-Hodgkin lymphoma (NHL) or chronic lymphocytic leukemia (CLL). Twenty-four patients, enrolled into 3 cohorts, including 6 patients who were positive for the C481S mutation, received GDC-0853 at 100, 200, or 400 mg once daily, orally...
February 27, 2018: Oncotarget
Kristina Busygina, Janina Jamasbi, Till Seiler, Hans Deckmyn, Christian Weber, Richard Brandl, Reinhard Lorenz, Wolfgang Siess
Interaction of Von Willebrand factor (VWF) with platelet glycoprotein (GP) Ib and of collagen with GPVI is essential for thrombus formation on ruptured or eroded atherosclerotic plaques (atherothrombosis). GPIb and GPVI signal through Bruton tyrosine kinase (Btk) which can irreversibly be blocked by oral application of ibrutinib, an established therapy for chronic lymphocytic leukemia (CLL) with long term safety. We found that ibrutinib and the novel Btk-inhibitors acalabrutinib and ONO/GS-4059 block GPVI-dependent static platelet aggregation in blood exposed to human plaque homogenate and collagen but not to ADP or arachidonic acid...
March 20, 2018: Blood
Lv Jiahui, Wu Jingde, He Feng, Qu Ying, Zhang Qiuqiong, Yu Chenggong
Rheumatoid Arthritis (RA) is a chronic autoimmune disease and becomes one of the major causes of disability and work force loss. The presence of abnormal B cell and autoantibodies produced by most RA patients, primarily ACPA and RF, indicate that the function of B cell was involved in the development of RA disease. Accordingly, the drug targeting B cell has become a hot spot in the treatment of RA. Studies have shown that Bruton's tyrosine kinase (BTK) is involved in the regulation of B cell proliferation and activation process...
March 16, 2018: Current Medicinal Chemistry
Yangyang Gu, Bo Huang, Yanfei Yang, Mengdie Qi, Guohua Lu, Dajing Xia, Hequan Li
Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible lung disease with high mortality rate. The etiology is unknown and treatment choices are limited. Thus, there is great interest to investigate novel agents for IPF therapy. Ibrutinib, BTK, and ITK irreversible inhibitor is a FDA-approved small molecule for the clinical therapy of B cell lymphoma. Its role in pulmonary fibrosis remains unknown. In this study, we investigated the anti-fibrotic activity of ibrutinib. Strikingly, ibrutinib did not inhibit but exacerbated bleomycin-induced pulmonary fibrosis by increased epithelial cell apoptosis, and inflammation in the lung...
March 13, 2018: Inflammation
Jon M Florence, Agnieszka Krupa, Laela M Booshehri, Sandra A Davis, Michael A Matthay, Anna K Kurdowska
Infection with seasonal influenza A virus (IAV) leads to lung inflammation and respiratory failure, a main cause of death in influenza infected patients. Previous experiments in our laboratory indicated that Bruton's tyrosine kinase (Btk) plays a substantial role in regulating inflammation in the respiratory region during acute lung injury (ALI) in mice, therefore we sought to determine if blocking Btk activity had a protective effect in the lung during influenza induced inflammation. A Btk inhibitor (Btk Inh...
March 8, 2018: American Journal of Physiology. Lung Cellular and Molecular Physiology
Gesmar R S Segundo, Anh T V Nguyen, Huyen T Thuc, Le N Q Nguyen, Roger H Kobayashi, Hai T Le, Huong T M Le, Troy R Torgerson, Hans D Ochs
Background: New sequencing techniques have revolutionized the identification of the molecular basis of primary immunodeficiency disorders (PID) not only by establishing a gene-based diagnosis but also by facilitating defect-specific treatment strategies, improving quality of life and survival, and allowing factual genetic counseling. Because these techniques are generally not available for physicians and their patients residing in developing countries, collaboration with overseas laboratories has been explored as a possible, albeit cumbersome, strategy...
2018: Frontiers in Immunology
Jiaji G Chen, Xia Liu, Manit Munshi, Lian Xu, Nicholas Tsakmaklis, Maria G Demos, Amanda Kofides, Maria Luisa Guerrera, Gloria G Chan, Christopher J Patterson, Kirsten E Meid, Joshua Gustine, Toni Dubeau, Patricia Severns, Jorge J Castillo, Zachary R Hunter, Jinhua Wang, Sara J Buhrlage, Nathanael S Gray, Steven P Treon, Guang Yang
Acquired ibrutinib resistance due to BTKCys481 mutations occurs in B-cell malignancies, including those with MYD88 mutations. BTKCys481 mutations are usually sub-clonal, and their relevance to clinical progression remains unclear. Moreover, the signaling pathways that promote ibrutinib resistance remain to be clarified. We therefore engineered BTKCys481Ser and BTKWT expressing MYD88 mutated WM and ABC DLBCL cells, and observed re-activation of BTK-PLCγ2-ERK1/2 signaling in the presence of ibrutinib in only the former...
March 1, 2018: Blood
Simon Vergnaud, Valéry-Pierre Riche, Philippe Tessier, Nicolas Mauduit, Adrien Kaladji, Yann Gouëffic
OBJECTIVES: To evaluate the budget impact of progressive replacement of standard polytetrafluoroethylene (PTFE) grafts by heparin-bound PTFE (Propaten) for below-the-knee (BTK) bypass in patients with critical limb ischaemia (CLI). DESIGN: From a review of the scientific literature, we calculated a theoretical BTK primary patency for Propaten grafts. Using the French hospital expenditure database (PMSI), we retrospectively estimated a rehospitalisation rate for standard PTFE grafts...
February 28, 2018: BMJ Open
Idanna Innocenti, Davide Rossi, Giulio Trapè, Francesco Autore, Luigi Maria Larocca, Vincenzo Gomes, Michaela Cerri, Paolo Falcucci, Simona Sica, Gianluca Gaidano, Luca Laurenti
Richter syndrome, a transformation of chronic lymphocytic leukemia (CLL) into a diffuse large B-cell lymphoma, is a rare complication of patients treated with chemo-immunotherapy. Richter syndrome might be both clonally related or unrelated to the underlying CLL and often showed mutations of the TP53 and NOTCH1 genes. Recently, ibrutinib was approved for patients with relapsed/refractory CLL or for untreated CLL patients with del 17p or TP53 mutation. The clinical picture, pathology, and genetics of Richter transformation after IBR treatment are largely unknown...
February 27, 2018: Hematological Oncology
Ann E Herman, Leslie W Chinn, Shweta G Kotwal, Elaine R Murray, Rui Zhao, Marilyn Florero, Alyse Lin, Anita Moein, Rena Wang, Meire Bremer, Serika Kokubu, Adrian P Serone, Eva L Hanze, Anders Viberg, Alyssa M Morimoto, Helen R Winter, Tamiko R Katsumoto
GDC-0853 is a small molecule inhibitor of Bruton's tyrosine kinase (BTK) that is highly selective and non-covalent, leading to reversible binding. In double-blind, randomized, and placebo-controlled phase I healthy volunteer studies, GDC-0853 was well-tolerated with no dose-limiting adverse events (AEs) or serious AEs. The maximum tolerated dose was not reached during dose escalation (≤600 mg, single ascending dose [SAD] study; ≤250 mg twice daily [BID] and ≤500 mg once daily, 14-day multiple ascending dose (MAD) study)...
February 27, 2018: Clinical Pharmacology and Therapeutics
Xinwei Liu, Jingdong Zhang, Wenfeng Han, Yu Wang, Yunen Liu, Yubiao Zhang, Dapeng Zhou, Liangbi Xiang
Subsequent to the publication of the above paper, the authors realize that they did not acknowledge their funders in their paper. Consequently, the following information should have been included in the published article: "Funding: This study was supported by a grant from the National Natural Science Foundation of China (no. 81401586)". The authors sincerely apologize for this mistake, and regret the inconvenience this omission has caused, including that to the funders of this study. [the original article was published in the Molecular Medicine Reports 16: 192-200, 2017; DOI: 10...
February 21, 2018: Molecular Medicine Reports
Lindsay E Nyhoff, Emily S Clark, Bridgette L Barron, Rachel H Bonami, Wasif N Khan, Peggy L Kendall
Bruton's tyrosine kinase (Btk) is a crucial regulator of B cell signaling and is a therapeutic target for lymphoma and autoimmune disease. BTK-deficient patients suffer from humoral immunodeficiency, as their B cells fail to progress beyond the bone marrow. However, the role of Btk in fully developed, mature peripheral B cells is not well understood. Analysis using BTK inhibitors is complicated by suboptimal inhibition, off-target effects, or failure to eliminate BTK's adaptor function. Therefore a Btk flox /Cre-ERT2 mouse model was developed and used to excise Btk after B cell populations were established...
February 26, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
Jiyu Guan, Dan Huang, Konstantin Yakimchuk, Sam Okret
Acquired resistance to cancer drugs is common, also for modern targeted drugs like the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, a new drug approved for the treatment of the highly aggressive and relapsing mantle cell lymphoma (MCL). The tumor microenvironment often impacts negatively on drug response. Here we demonstrate that stromal cells protect MCL cells from ibrutinib-induced apoptosis and support MCL cell regrowth after drug removal by impairing ibrutinib-mediated down-regulation of phosphoinositide-3-kinase (PI3K)/AKT signaling...
February 26, 2018: Molecular Cancer Therapeutics
Craig S Boddy, Shuo Ma
PURPOSE OF REVIEW: Chronic lymphocytic leukemia (CLL) has multiple current frontline therapy options, including chemoimmunotherapy (CIT) and most recently, ibrutinib. Here, we review the most recent updates in the frontline treatment of CLL, including updates in CIT, updates in targeted therapies, and ongoing clinical trials. RECENT FINDINGS: Ibrutinib was FDA-approved for the upfront treatment of CLL in 2016 after being studied in older patients and those with 17p deletions or TP53 mutations...
February 26, 2018: Current Hematologic Malignancy Reports
Lauriane Goldwirt, Kevin Beccaria, Alain Ple, Hélène Sauvageon, Samia Mourah
PURPOSE: Central nervous system (CNS) dissemination occurs in 4.1% of mantle cell lymphoma (MCL) patients and clinically significant CNS involvement in chronic lymphocytic leukemia (CLL) patients reaches 4%. Ibrutinib, an orally administered Bruton's tyrosine kinase (BTK) inhibitor, has shown substantial activity in CLL or MCL patients with CNS localization, and in primary central nervous system lymphoma (PCNSL). The drug efficacy to treat primary or secondary CNS impairments relies on its brain distribution through the blood-brain barrier (BBB), the aim of the present work was to study the brain distribution of ibrutinib using an in vivo mice model...
February 23, 2018: Cancer Chemotherapy and Pharmacology
Riccardo Bomben, Simone Ferrero, Tiziana D'Agaro, Michele Dal Bo, Alessandro Re, Andrea Evangelista, Angelo Michele Carella, Alberto Zamò, Umberto Vitolo, Paola Omedè, Chiara Rusconi, Luca Arcaini, Luigi Rigacci, Stefano Luminari, Andrea Piccin, Delong Liu, Adrien Wiestner, Gianluca Gaidano, Sergio Cortelazzo, Marco Ladetto, Valter Gattei
Mantle cell lymphoma patients have variable clinical courses, ranging from indolent cases not requiring immediate treatment to aggressive, rapidly progressing diseases. Thus, diagnostic tools capable to stratify patients according to their risk of relapse and death are warranted. The study included 83 samples from the Fondazione Italiana Linfomi MCL-0208 clinical trial. Through gene expression profiling and quantitative real-time PCR we analyzed 46 peripheral blood and 43 formalin-fixed paraffin-embedded lymph node samples...
February 22, 2018: Haematologica
Yuanzhi Xu, Song Gu, Yunke Bi, Xiangqian Qi, Yujin Yan, Meiqing Lou
Glioma is a severe disease of the central nervous system. Although previous studies have identified the important role of the immune response in association with tumor intervention, it is still unknown whether PU.1, a transcription factor known for its role in myeloid differentiation and immune responses, is involved in the progression of glioma. In the present study, we found a significant increase in SPI1, the gene that encodes PU.1, in samples from patients with glioma. Through genotype-phenotype association analysis several candidate factors that may mediate the role of PU...
March 2018: Oncology Letters
James J Crawford, Adam R Johnson, Dinah L Misner, Lisa D Belmont, Georgette M Castanedo, Regina Choy, Melis Coraggio, Liming Dong, Charles Eigenbrot, Rebecca Erickson, Nico Ghilardi, Jonathan Hau, Arna Katewa, Pawan Bir Kohli, Wendy Lee, Joseph W Lubach, Brent S McKenzie, Daniel Fred Ortwine, Leah Schutt, Suzanne Tay, Binqing Wei, Karin Reif, Lichuan Liu, Harvey Wong, Wendy B Young
Btk is a non-receptor cytoplasmic tyrosine kinase involved in B-cell and myeloid cell activation, downstream of B-cell and Fcγ receptors, respectively. Pre-clinical studies have indicated that inhibition of Btk activity might offer a potential therapy in autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. Here we disclose the discovery and pre-clinical characterization of a potent, selective, and non-covalent Btk inhibitor currently in clinical development. GDC-0853 (29) suppresses B cell- and myeloid cell-mediated components of disease, and demonstrates dose-dependent activity in an in vivo rat model of inflammatory arthritis...
February 19, 2018: Journal of Medicinal Chemistry
Simar Pal Singh, Floris Dammeijer, Rudi W Hendriks
Bruton's tyrosine kinase (BTK) is a non-receptor kinase that plays a crucial role in oncogenic signaling that is critical for proliferation and survival of leukemic cells in many B cell malignancies. BTK was initially shown to be defective in the primary immunodeficiency X-linked agammaglobulinemia (XLA) and is essential both for B cell development and function of mature B cells. Shortly after its discovery, BTK was placed in the signal transduction pathway downstream of the B cell antigen receptor (BCR). More recently, small-molecule inhibitors of this kinase have shown excellent anti-tumor activity, first in animal models and subsequently in clinical studies...
February 19, 2018: Molecular Cancer
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