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Ibrutinib

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https://www.readbyqxmd.com/read/28938632/the-%C3%AE-secretase-inhibitors-enhance-the-anti-leukemic-activity-of-ibrutinib-in-b-cll-cells
#1
Paola Secchiero, Rebecca Voltan, Erika Rimondi, Elisabetta Melloni, Emmanouil Athanasakis, Veronica Tisato, Stefania Gallo, Gian Matteo Rigolin, Giorgio Zauli
Ibrutinib blocks B-cell receptor signaling and interferes with leukemic cell-to-microenvironment interactions. Ibrutinib plays a key role in the management of B-CLL and is recommended for first line treatment of high-risk CLL patients with 17p deletion. Therefore, elucidating the factors governing sensitivity/resistance to Ibrutinib represents a relevant issue. For this purpose, in 3 B-CLL patient samples harboring functional TP53 mutations, the frequency of the mutated clones was monitored during in vivo Ibrutinib therapy, revealing a progressive decline of the frequency of TP53(mut) clones during 12 months of treatment...
August 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28933554/rational-targeting-of-cellular-cholesterol-in-diffuse-large-b-cell-lymphoma-dlbcl-enabled-by-functional-lipoprotein-nanoparticles-a-therapeutic-strategy-dependent-on-cell-of-origin
#2
Jonathan S Rink, Shuo Yang, Osman Cen, Tim Taxter, Kaylin M McMahon, Sol Misener, Amir Behdad, Richard Longnecker, Leo I Gordon, C Shad Thaxton
Cancer cells have altered metabolism and, in some cases, an increased demand for cholesterol. It is important to identify novel, rational treatments based on biology, and cellular cholesterol metabolism as a potential target for cancer is an innovative approach. Toward this end, we focused on diffuse large B-cell lymphoma (DLBCL) as a model because there is differential cholesterol biosynthesis driven by B-cell receptor (BCR) signaling in germinal center (GC) versus activated B-cell (ABC) DLBCL. To specifically target cellular cholesterol homeostasis, we employed high-density lipoprotein-like nanoparticles (HDL NP) that can generally reduce cellular cholesterol by targeting and blocking cholesterol uptake through the high-affinity HDL receptor, scavenger receptor type B-1 (SCARB1)...
September 21, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28924018/ibrutinib-for-chronic-graft-versus-host-disease-after-failure-of-prior-therapy
#3
David Miklos, Corey S Cutler, Mukta Arora, Edmund K Waller, Madan Jagasia, Iskra Pusic, Mary E Flowers, Aaron C Logan, Ryotaro Nakamura, Bruce R Blazar, Yunfeng Li, Stephen Chang, Indu Lal, Jason Dubovsky, Danelle F James, Lori Styles, Samantha Jaglowski
Chronic graft-versus-host disease (cGVHD) is a serious complication of allogeneic stem cell transplantation with few effective options available after failure of corticosteroids. B and T cells play a role in the pathophysiology of cGVHD. Ibrutinib inhibits Bruton's tyrosine kinase in B cells and interleukin-2-inducible T-cell kinase in T cells. In preclinical models, ibrutinib reduced severity of cGVHD. This multicenter, open-label study evaluated the safety and efficacy of ibrutinib in patients with active cGVHD with inadequate response to corticosteroid-containing therapies...
September 18, 2017: Blood
https://www.readbyqxmd.com/read/28922238/primary-central-nervous-system-lymphoma-time-for-diagnostic-biomarkers-and-biotherapies
#4
Louis Royer-Perron, Khê Hoang-Xuan, Agusti Alentorn
PURPOSE OF REVIEW: Primary central nervous system lymphoma (PCNSL) is a rare cancer with a somber prognosis in older patients, which it affects predominantly. Only in recent years have molecular alterations characterizing PCNSL been thoroughly described. This opens possibilities for the use of targeted therapies. Developments in imaging and biomarkers have also great potential to help clinicians faced with diagnostic and prognostic uncertainties. RECENT FINDINGS: Several biomarkers for PCNSL, such as different microRNAs, which could be tested in cerebrospinal fluid and vitreous fluid, and IL-10, which has been shown to have excellent sensitivity and specificity in the cerebrospinal fluid, have emerged in the last years...
September 15, 2017: Current Opinion in Neurology
https://www.readbyqxmd.com/read/28921505/nfatc1-activation-by-dna-hypomethylation-in-chronic-lymphocytic-leukemia-correlates-with-clinical-staging-and-can-be-inhibited-by-ibrutinib
#5
Christine Wolf, Angela Garding, Katharina Filarsky, Jasmin Bahlo, Sandra Robrecht, Natalia Becker, Manuela Zucknick, Arefeh Rouhi, Anja Weigel, Rainer Claus, Dieter Weichenhan, Barbara Eichhorst, Kirsten Fischer, Michael Hallek, Florian Kuchenbauer, Christoph Plass, Hartmut Döhner, Stephan Stilgenbauer, Peter Lichter, Daniel Mertens
B cell receptor (BCR) signaling is key for survival of chronic lymphocytic leukemia (CLL) cells, and BCR signaling inhibitors are clinically active. However, relapse and resistance to treatment require novel treatment options. In order to detect novel candidate therapeutic targets, we performed a genome-wide DNA methylation screen with custom arrays and identified aberrant promoter DNA methylation in 2192 genes. The transcription factor NFATC1 that is a downstream effector of BCR signaling was among the top hypomethylated genes and was concomitantly transcriptionally upregulated in CLL...
September 18, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/28918995/cutaneous-adverse-events-of-targeted-therapies-for-hematolymphoid-malignancies
#6
REVIEW
Julia D Ransohoff, Bernice Y Kwong
The identification of oncogenic drivers of liquid tumors has led to the rapid development of targeted agents with distinct cutaneous adverse event (AE) profiles. The diagnosis and management of these skin toxicities has motivated a novel partnership between dermatologists and oncologists in developing supportive oncodermatology clinics. In this article we review the current state of knowledge of clinical presentation, mechanisms, and management of the most common and significant cutaneous AEs observed during treatment with targeted therapies for hematologic and lymphoid malignancies...
July 14, 2017: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/28910460/sudden-flank-pain-in-a-patient-receiving-ibrutinib-for-mantle-cell-lymphoma
#7
Yu Xi Terence Law, Lui Shiong Lee
No abstract text is available yet for this article.
September 14, 2017: JAMA Oncology
https://www.readbyqxmd.com/read/28905990/the-mtor-kinase-inhibitor-everolimus-synergistically-enhances-the-anti-tumor-effect-of-the-bruton-s-tyrosine-kinase-btk-inhibitor-pls-123-on-mantle-cell-lymphoma
#8
Jiao Li, Xiaogan Wang, Yan Xie, Zhitao Ying, Weiping Liu, Lingyan Ping, Chen Zhang, Zhengying Pan, Ning Ding, Yuqin Song, Jun Zhu
Mantle cell lymphoma (MCL) is an aggressive and incurable malignant disease. Despite of general chemotherapy, relapse and mortality are common, highlighting the need for the development of novel targeted drugs or combination of therapeutic regimens. Recently, several drugs that target the B-cell receptor (BCR) signaling pathway, especially the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, have demonstrated notable therapeutic effects in relapsed/refractory patients, which indicate that pharmacological inhibition of BCR pathway holds promise in MCL treatment...
September 14, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/28901789/cardiac-side-effects-of-bruton-tyrosine-kinase-btk-inhibitors
#9
Chloe Pek Sang Tang, Julie McMullen, Constantine Tam
The development of bruton tyrosine kinase inhibitors (BTKi) has been a significant advancement in the treatment of chronic lymphocytic leukemia and related B-cell malignancies. As experience in using ibrutinib increased, the first drug to be licensed in its class, atrial fibrillation (AF) emerged as an important side effect. The intersection between BTKi therapy for B-cell malignancies and AF represents a complex area of management with scant evidence for guidance. Consideration needs to be taken regarding the interplay of increased bleeding risk versus thromboembolic complications of AF, drug interactions between ibrutinib and anticoagulants and antiarrhythmic agents, and the potential for other, as yet seldom reported cardiac side effects...
September 13, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28891366/efficacy-and-safety-of-b-cell-receptor-signaling-pathway-inhibitors-in-relapsed-refractory-chronic-lymphocytic-leukemia-a-systematic-review-and-meta-analysis-of-randomized-clinical-trials
#10
Anna Puła, Konrad Stawiski, Marcin Braun, Elżbieta Iskierka-Jażdżewska, Tadeusz Robak
Ibrutinib and idelalisib, B-cell receptor (BCR) signaling pathway inhibitors, have been recently approved for use against relapsed/refractory chronic lymphocytic leukemia (CLL). To assess the efficacy and safety of BCR pathway inhibitors in relapsed/refractory CLL, we conducted a systematic review and meta-analysis of five randomized controlled trials (1866 patients). Our study demonstrated that BCR pathway inhibitors significantly prolonged progression-free survival (PFS; pooled HR = 0.24; 95% CI: 0.19-0...
September 11, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28882879/acalabrutinib-acp-196-a-covalent-bruton-tyrosine-kinase-btk-inhibitor-with-a-differentiated-selectivity-and-in-vivo-potency-profile
#11
Tjeerd Barf, Todd Covey, Raquel Izumi, Bas van de Kar, Michael Gulrajani, Bart van Lith, Maaike van Hoek, Edwin de Zwart, Diana Mittag, Dennis Demont, Saskia Verkaik, Fanny Krantz, Paul G Pearson, Roger Ulrich, Allard Kaptein
Several small-molecule BTK inhibitors are in development for B-cell malignancies and autoimmune disorders, each characterized by distinct potency and selectivity patterns. Herein we describe the pharmacologic characterization of BTK inhibitor acalabrutinib (1, ACP-196). Acalabrutinib possesses a reactive butynamide group that binds covalently to Cys481 in BTK. Relative to the other BTK inhibitors described here, the reduced intrinsic reactivity of acalabrutinib helps to limit inhibition of off-target kinases having cysteine-mediated covalent binding potential...
September 7, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28876896/differential-kinobeads-profiling-for-target-identification-of-irreversible-kinase-inhibitors
#12
Lars Dittus, Thilo Werner, Marcel Muelbaier, Marcus Bantscheff
Chemoproteomics profiling of kinase inhibitors with kinobeads enables the assessment of inhibitor potency and selectivity for endogenously expressed protein kinases in cell lines and tissues. Using a small panel of targeted covalent inhibitors, we demonstrate the importance of measuring covalent target binding in live cells. We present a differential kinobeads profiling strategy for covalent kinase inhibitors where a compound is added either to live cells or to a cell extract that enables the comprehensive assessment of inhibitor selectivity for covalent and noncovalent targets...
September 12, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28864640/spotlight-on-ibrutinib-in-pcnsl-adding-another-feather-to-its-cap
#13
Aparna Lakshmanan, John C Byrd
In this issue Grommes and colleagues elegantly show that the irreversible inhibitor of Bruton tyrosine kinase, ibrutinib, promotes a high proportion of durable responses in primary central nervous system lymphoma, a type of diffuse large B-cell lymphoma (DLBCL), and also in secondary DLBCL relapsing to the central nervous system. Mutations in the B-cell antigen receptor-associated protein CD79B with upregulation of the MTOR pathway were associated with diminished response, but preclinical combination of PIK3CA and PIK3CD inhibitors synergized with ibrutinib to overcome this resistance mechanism, providing opportunity for further targeted therapy of this difficult-to-treat disease...
September 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28860341/targeting-metabolism-and-survival-in-chronic-lymphocytic-leukemia-and-richter-syndrome-cells-by-a-novel-nf-kb-inhibitor
#14
Tiziana Vaisitti, Federica Gaudino, Samedy Ouk, Maria Moscvin, Nicoletta Vitale, Sara Serra, Francesca Arruga, Johannes L Zakrzewski, Hsiou-Chi Liou, John N Allan, Richard R Furman, Silvia Deaglio
IT-901 is a novel and selective NF-kB inhibitor with promising activity in pre-clinical models. Here we show that treatment of chronic lymphocytic leukemia cells with IT-901 effectively interrupts NF-kB transcriptional activity. Chronic lymphocytic leukemia cells exposed to the drug display elevated mitochondrial reactive oxygen species, which damage mitochondria, limit oxidative phosphorylation and ATP production and activate intrinsic apoptosis. Inhibition of NF-kB signaling in stromal and myeloid cells, both tumor-supportive elements, fails to induce apoptosis, but impairs NF-kB-driven expression of molecules involved in cell-cell contacts and immune responses, essential elements in creating a pro-leukemic niche...
August 31, 2017: Haematologica
https://www.readbyqxmd.com/read/28858511/anchimerically-activated-protides-as-inhibitors-of-cap-dependent-translation-and-inducers-of-chemosensitization-in-mantle-cell-lymphoma
#15
Aniekan Okon, JingJing Han, Surendra Dawadi, Christos Demosthenous, Courtney C Aldrich, Mamta Gupta, Carston R Wagner
The cellular delivery of nucleotides through various pronucleotide strategies has expanded the utility of nucleosides as a therapeutic class. Although highly successful, the highly popular ProTide system relies on a four-step enzymatic and chemical process to liberate the corresponding monophosphate. To broaden the scope and reduce the number of steps required for monophosphate release, we have developed a strategy that depends on initial chemical activation by a sulfur atom of a methylthioalkyl protecting group, followed by enzymatic hydrolysis of the resulting phosphoramidate monoester...
September 20, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28851760/tumor-lysis-syndrome-in-chronic-lymphocytic-leukemia-with-novel-targeted-agents
#16
Bruce D Cheson, Sari Heitner Enschede, Elisa Cerri, Monali Desai, Jalaja Potluri, Nicole Lamanna, Constantine Tam
Tumor lysis syndrome (TLS) is an uncommon but potentially life-threatening complication associated with the treatment of some cancers. If left untreated, TLS may result in acute renal failure, cardiac dysrhythmia, neurologic complications, seizures, or death. Tumor lysis syndrome is most commonly observed in patients with hematologic malignancies with a high proliferation rate undergoing treatment with very effective therapies. In chronic lymphocytic leukemia (CLL), historically, TLS has been observed less often, owing to a low proliferation rate and slow response to chemotherapy...
August 29, 2017: Oncologist
https://www.readbyqxmd.com/read/28849690/efficacy-of-ibrutinib-in-a-patient-with-transformed-lymphoplasmacytic-lymphoma-and-central-nervous-system-involvement
#17
Laura S Hiemcke-Jiwa, Roos J Leguit, Joyce H Radersma-van Loon, Peter E Westerweel, Johannes J M Rood, Jeanette K Doorduijn, Manon M H Huibers, Monique C Minnema
No abstract text is available yet for this article.
August 29, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28841589/role-of-stem-cell-transplant-in-lymphoma-in-the-era-of-new-drugs
#18
Katerina Benekou, Silvia Montoto
PURPOSE OF REVIEW: Better understanding of the lymphoma pathogenesis and molecular biology has introduced a new era in the lymphoma therapy with the advent of targeted drugs. In this new era, the role of hematopoietic stem cell transplantation (HSCT) is evolving, and the purpose of this review is to demonstrate how the introduction of novel agents has affected the current treatment strategy of different subtypes of lymphoma. RECENT FINDINGS: Autologous stem cell transplantation (ASCT) remains the standard of care for patients with relapsed Hodgkin Lymphoma and high-grade non-Hodgkin lymphoma (NHL)...
August 24, 2017: Current Opinion in Oncology
https://www.readbyqxmd.com/read/28835384/ezh2-inhibition-by-tazemetostat-results-in-altered-dependency-on-b-cell-activation-signaling%C3%A2-in-dlbcl
#19
Dorothy Brach, Danielle Johnston-Blackwell, Allison Drew, Trupti Lingaraj, Vinny Motwani, Natalie M Warholic, Igor Feldman, Christopher Plescia, Jesse J Smith, Robert A Copeland, Heike Keilhack, Elayne Chan-Penebre, Sarah K Knutson, Scott A Ribich, Alejandra Raimondi, Michael J Thomenius
The EZH2 small molecule inhibitor tazemetostat (EPZ-6438) is currently being evaluated in phase II clinical trials for the treatment of non-Hodgkin's Lymphoma (NHL).  We have previously shown that EZH2 inhibitors display an anti-proliferative effect in multiple pre-clinical models of NHL, and that models bearing gain-of-function mutations in EZH2 were consistently more sensitive to EZH2 inhibition than lymphomas with wild-type (WT) EZH2 Here, we demonstrate that cell lines bearing EZH2 mutations show a cytotoxic response, while cell lines with WT-EZH2 show a cytostatic response and only tumor growth inhibition without regression in a xenograft model...
August 23, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28832957/outcomes-in-370-patients-with-mantle-cell-lymphoma-treated-with-ibrutinib-a-pooled-analysis-from-three-open-label-studies
#20
Simon Rule, Martin Dreyling, Andre Goy, Georg Hess, Rebecca Auer, Brad Kahl, Nora Cavazos, Black Liu, Shiyi Yang, Fong Clow, Jenna D Goldberg, Darrin Beaupre, Jessica Vermeulen, Mark Wildgust, Michael Wang
Ibrutinib is highly active in treating mantle cell lymphoma (MCL), an aggressive B-cell lymphoma. We pooled data from three ibrutinib studies to explore the impact of baseline patient characteristics on treatment response. Patients with relapsed/refractory MCL (n = 370) treated with ibrutinib had an objective response rate (ORR) of 66% (20% complete response; 46% partial response); median duration of response (DOR), progression-free survival (PFS) and overall survival (OS) were 18·6, 12·8 and 25·0 months, respectively...
August 18, 2017: British Journal of Haematology
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