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Idelalisib

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https://www.readbyqxmd.com/read/29235459/pi3k%C3%AE-activates-e2f1-synthesis-in-response-to-mrna-translation-stress
#1
Sivakumar Vadivel Gnanasundram, Slovénie Pyndiah, Chrysoula Daskalogianni, Kate Armfield, Karin Nylander, Joanna B Wilson, Robin Fåhraeus
The c-myc oncogene stimulates ribosomal biogenesis and protein synthesis to promote cellular growth. However, the pathway by which cells sense and restore dysfunctional mRNA translation and how this is linked to cell proliferation and growth is not known. We here show that mRNA translation stress in cis triggered by the gly-ala repeat sequence of Epstein-Barr virus (EBV)-encoded EBNA1, results in PI3Kδ-dependent induction of E2F1 mRNA translation with the consequent activation of c-Myc and cell proliferation...
December 13, 2017: Nature Communications
https://www.readbyqxmd.com/read/29233821/activity-of-the-pi3k-%C3%AE-%C3%AE-inhibitor-duvelisib-in-a-phase-i-trial-and-preclinical-models-of-t-cell-lymphoma
#2
Steven M Horwitz, Raphael Koch, Pierluigi Porcu, Yasuhiro Oki, Alison Moskowitz, Megan Perez, Patricia Myskowski, Adam Officer, Jacob D Jaffe, Sara N Morrow, Kerstin Allen, Mark Douglas, Howard Stern, Jennifer Sweeney, Patrick Kelly, Virginia Kelly, Jon C Aster, David Weaver, Francine M Foss, David M Weinstock
Duvelisib (IPI-145) is an oral inhibitor of phosphoinositide-3-kinase (PI3K)-δ/γ isoforms currently in clinical development. PI3K-δ/γ inhibition may directly inhibit malignant T-cell growth, making Duvelisib a promising candidate for patients with peripheral (PTCL) or cutaneous (CTCL) T-cell lymphoma. Inhibition of either isoform may also contribute to clinical responses by modulating nonmalignant immune cells. We investigated these dual effects in a TCL cohort from a Phase 1, open-label study of Duvelisib in patients with relapsed or refractory PTCL [n=16] and CTCL [n=19], along with in vitro and in vivo models of TCL...
December 12, 2017: Blood
https://www.readbyqxmd.com/read/29230799/a-retrospective-study-on-the-management-of-patients-with-rituximab-refractory-follicular-lymphoma
#3
Philippe Solal-Céligny, Pierre Leconte, Aurélie Bardet, Juana Hernandez, Xavier Troussard
Given that there are currently no clear recommendations regarding therapeutic options for rituximab refractory/relapsed follicular lymphoma patients, this study aimed to describe the real-life management of patients with refractory follicular lymphoma after systemic rituximab-containing regimens (rFL), and rFL patient characteristics. In this retrospective, national, multicentre study, descriptive analyses were mainly performed according to rituximab-containing regimen at rFL diagnosis [rituximab monotherapy (R-MONO), rituximab + chemotherapy (R-COMBO), and ongoing rituximab maintenance (R-MAINTAIN)]...
December 12, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/29226472/cost-utility-analysis-of-idelalisib-in-combination-with-rituximab-in-relapsed-or-refractory-chronic-lymphocytic-leukaemia
#4
Luis Felipe Casado, José Ángel Hernández, Isidro Jarque, María Echave, Miguel Angel Casado, Antonio Castro
OBJECTIVE: To evaluate the incremental cost-utility ratio (ICUR) of idelalisib in combination with rituximab (IR) versus rituximab monotherapy (R) in the treatment of patients with relapsed or refractory (R/R) chronic lymphocytic leukaemia (CLL), from the Spanish National Health System (NHS) perspective. METHODS: A partitioned survival Markov model for a lifetime horizon (30 years) was developed to estimate costs (€, 2016) and quality-adjusted life years (QALY) with IR and R...
December 11, 2017: European Journal of Haematology
https://www.readbyqxmd.com/read/29222670/venetoclax-for-treating-chronic-lymphocytic-leukaemia-an-evidence-review-group-perspective-of-a-nice-single-technology-appraisal
#5
REVIEW
Hema Mistry, Chidozie Nduka, Martin Connock, Jill Colquitt, Theodoros Mantopoulos, Emma Loveman, Renata Walewska, James Mason
Venetoclax is licensed to treat relapsed or refractory (R/R) chronic lymphocytic leukaemia (CLL). As part of the Single Technology Appraisal (STA) ID944, the National Institute for Health and Care Excellence (NICE) invited AbbVie, the manufacturer, to submit evidence on the use of venetoclax, within its licensed indication. The Evidence Review Group (ERG), Warwick Evidence, was asked to provide an independent and critical review of the submitted evidence. Evidence came from three single-arm trials in CLL patients with or without 17p deletion [del(17p])/TP53 chromosomal abnormalities...
December 8, 2017: PharmacoEconomics
https://www.readbyqxmd.com/read/29222277/how-should-we-sequence-and-combine-novel-therapies-in-cll
#6
REVIEW
Matthew S Davids
With the recent approval of several effective and well-tolerated novel agents (NAs), including ibrutinib, idelalisib, venetoclax, and obinutuzumab, patients with chronic lymphocytic leukemia (CLL) have more therapeutic options than ever before. The availability of these agents is both an important advance for patients but also a challenge for practicing hematologist/oncologists to learn how best to sequence NAs, both with respect to chemoimmunotherapy (CIT) and to other NAs. The sequencing of NAs in clinical practice should be guided both by an individual patient's prognostic markers, such as FISH and immunoglobulin heavy chain variable region (IGHV)-mutation status, as well as the patient's medical comorbidities and goals of care...
December 8, 2017: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/29222275/the-mutational-landscape-of-chronic-lymphocytic-leukemia-and-its-impact-on-prognosis-and-treatment
#7
REVIEW
Gianluca Gaidano, Davide Rossi
The typical genome of chronic lymphocytic leukemia (CLL) carries ∼2000 molecular lesions. Few mutations recur across patients at a frequency >5%, whereas a large number of biologically and clinically uncharacterized genes are mutated at lower frequency. Approximately 80% of CLL patients carry at least 1 of 4 common chromosomal alterations, namely deletion 13q14, deletion 11q22-23, deletion 17p12, and trisomy 12. Knowledge of the CLL genome has translated into the availability of molecular biomarkers for prognosis and treatment prediction...
December 8, 2017: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/29196709/lck-is-a-relevant-target-in-chronic-lymphocytic-leukaemia-cells-whose-expression-variance-is-unrelated-to-disease-outcome
#8
Kathleen J Till, John C Allen, Fatima Talab, Ke Lin, David Allsup, Lynn Cawkwell, Alison Bentley, Ingo Ringshausen, Andrew D Duckworth, Andrew R Pettitt, Nagesh Kalakonda, Joseph R Slupsky
Pathogenesis of chronic lymphocytic leukaemia (CLL) is contingent upon antigen receptor (BCR) expressed by malignant cells of this disease. Studies on somatic hypermutation of the antigen binding region, receptor expression levels and signal capacity have all linked BCR on CLL cells to disease prognosis. Our previous work showed that the src-family kinase Lck is a targetable mediator of BCR signalling in CLL cells, and that variance in Lck expression associated with ability of BCR to induce signal upon engagement...
December 1, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29179250/pi3k-inhibitors-understanding-toxicity-mechanisms-and-management
#9
REVIEW
I Brian Greenwell, Andrew Ip, Jonathon B Cohen
The phosphatidylinositol 3-kinase (PI3K) pathway has attracted immense interest as a therapeutic target for cancer treatment. Idelalisib was the first PI3K inhibitor approved by the US Food and Drug Administration and is utilized in the treatment of relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma and follicular lymphoma. Copanlisib has subsequently been approved for relapsed follicular lymphoma in patients who have received at least two prior systemic therapies. There are multiple other PI3K agents currently in development; these target various combinations of PI3K isoforms...
November 15, 2017: Oncology (Williston Park, NY)
https://www.readbyqxmd.com/read/29164976/ibrutinib-and-idelalisib-block-immunophenotypic-changes-associated-with-the-adhesion-and-activation-of-cll-cells-in-the-tumor-microenvironment
#10
Yandong Shen, O Giles Best, Stephen P Mulligan, Richard I Christopherson
The lymph node and bone marrow microenvironments promote the survival and proliferation of CLL cells. Defining the immunophenotype of CLL cells from the tumor microenvironment may help to better understand the mechanisms of action of current therapies and identify novel drug targets. Significant changes in the levels of 25 CD antigens were identified using the DotScan™ antibody microarray following CLL-cell culture with CD40L-expressing fibroblasts. Ibrutinib or idelalisib countered the change in expression of 11 of these antigens (CD23, CD27, CD53, CD58, CD71, CD80, CD84, CD97, CD126, CD150, and FMC7), which have known roles in cell activation and adhesion...
November 22, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/29163807/macitentan-a-double-antagonist-of-endothelin-receptors-efficiently-impairs-migration-and-microenvironmental-survival-signals-in-chronic-lymphocytic-leukemia
#11
Rossana Maffei, Stefania Fiorcari, Tiziana Vaisitti, Silvia Martinelli, Stefania Benatti, Giulia Debbia, Davide Rossi, Patrizia Zucchini, Leonardo Potenza, Mario Luppi, Gianluca Gaidano, Silvia Deaglio, Roberto Marasca
The crosstalk between chronic lymphocytic leukemia (CLL) cells and tumor microenvironment is essential for leukemic clone maintenance, supporting CLL cells survival, proliferation and protection from drug-induced apoptosis. Over the past years, the role of several soluble factors involved in these processes has been studied. CLL cells express higher levels of endothelin 1 (ET-1) and ETA receptor as compared to normal B cells. Upon ET-1 stimulation, CLL cells improve their survival and proliferation and reduce their sensitivity to the phosphoinositide-3-kinase δ inhibitor idelalisib and to fludarabine...
October 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/29150880/a-slowly-developed-severe-cutaneous-adverse-reaction-to-idelalisib
#12
L Huilaja, O Lindgren, M Soronen, T Siitonen, K Tasanen
Intracellular signal mediator phosphatidylinositol-3-kinase (PIK3K) -δ, an isoform of PIK3K, is expressed in hematopoietic cells especially in lymphoid lineage 1. Idelalisib is a novel PIK3K-δ targeted kinase inhibitor which is approved for relapsed follicular B-cell non-Hodgkin lymphoma as a monotherapy and in combination with rituximab, an anti-CD20 antibody, for relapsed chronic lymphocytic leukemia (CLL) 2. Only one case describing the clinical features of severe cutaneous adverse reaction (SCAR) of idelalisib in detail has been previously published 3...
November 17, 2017: Journal of the European Academy of Dermatology and Venereology: JEADV
https://www.readbyqxmd.com/read/29143108/immune-checkpoint-inhibitor-colitis-the-flip-side-of-the-wonder-drugs
#13
Naziheh Assarzadegan, Elizabeth Montgomery, Robert A Anders
Immune checkpoint inhibitors block the co-inhibitory receptors on T cells to activate their cytotoxic immune function and are rapidly being explored for the treatment of various advanced-stage malignancies. These novel drugs have already significantly increased survival rates. The first available immune checkpoint inhibitors were cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitors (such as ipilimumab), followed by programmed cell death protein 1 (PD-1) and programmed cell death protein ligand 1 (PD-L1) inhibitors (such as pembrolizumab and nivolumab)...
November 15, 2017: Virchows Archiv: An International Journal of Pathology
https://www.readbyqxmd.com/read/29122897/polymyalgia-rheumatica-development-in-a-patient-under-pi3k-inhibitor-therapy-for-chronic-lymphocytic-leukaemia
#14
Sanah Sajawal, Sarah L Mackie, Peter Hillmen, Dennis McGonagle
We report a patient with chronic lymphocytic leukaemia (CLL) who was treated with idelalisib, a PI3Kδ inhibitor with rituximab. After 20 weeks of treatment, the patient developed classical signs and symptoms of polymyalgia rheumatica (PMR) in association with an elevated C reactive protein of 74 mg/L. After 2 weeks of prednisolone 15 mg daily symptoms had resolved and acute phase markers normalised. To our knowledge, this is the first report of PMR developing as a complication of PI3Kδ inhibitor treatment of CLL...
November 8, 2017: BMJ Case Reports
https://www.readbyqxmd.com/read/29108275/functional-imaging-in-combination-with-mutation-status-aids-prediction-of-response-to-inhibiting-b-cell-receptor-signaling-in-lymphoma
#15
Laura Jacobs, Stefan Habringer, Jolanta Slawska, Katharina Huber, Elke Hauf, Zhoulei Li, Yosef Refaeli, Markus Schwaiger, Martina Rudelius, Axel Walch, Ulrich Keller
Aberrant B-cell receptor (BCR) signaling is known to contribute to malignant transformation. Two small molecule inhibitors targeting BCR pathway signaling include ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, and idelalisib, a specific Phosphatidylinositol-4,5-bisphosphate 3-kinase delta (PI3Kδ) inhibitor, both of which have been approved for use in haematological malignancies. Despite the identification of various diffuse large B-cell lymphoma (DLBCL) subtypes, mutation status alone is not sufficient to predict patient response and therapeutic resistance can arise...
October 3, 2017: Oncotarget
https://www.readbyqxmd.com/read/29097160/clinical-practice-guidelines-for-diagnosis-and-treatment-of-chronic-lymphocytic-leukemia-cll-in-the-netherlands
#16
Sabina Kersting, Suzanne I M Neppelenbroek, Hein P J Visser, Michel van Gelder, Mark-David Levin, Rogier Mous, Ward Posthuma, Hanneke M van der Straaten, Arnon P Kater
INTRODUCTION: In recent years, considerable progress has been made in the treatment of patients with chronic lymphocytic leukemia (CLL), and new potent drugs have become available. Therefore, the CLL working party revised the Dutch guidelines. Not only efficacy but also quality of life and socio-economic impact were taken into account in the formulation of treatment recommendations. MATERIALS AND METHODS: The working party discussed a set of questions regarding diagnostic tests and treatment and wrote the draft guideline...
September 25, 2017: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/29070613/copanlisib-produces-prolonged-responses-in-lymphoma
#17
(no author information available yet)
A phase II trial of the pan-class I PI3K inhibitor copanlisib demonstrated that it induces objective responses in 59% of patients with relapsed or refractory indolent lymphoma. The responses lasted a median of 22.6 months. Although the drugs weren't compared head to head, researchers suspect that the side effects of copanlisib may be less severe than those of idelalisib, another PI3K inhibitor.
October 25, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/29069762/cell-lines-generated-from-a-chronic-lymphocytic-leukemia-mouse-model-exhibit-constitutive-btk-and-akt-signaling
#18
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...
September 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/29066507/pqr309-is-a-novel-dual-pi3k-mtor-inhibitor-with-pre-clinical-antitumor-activity-in-lymphomas-as-a-single-agent-and-in-combination-therapy
#19
Chiara Tarantelli, Eugenio Gaudio, Alberto Jesus Arribas, Ivo Kwee, Petra Hillmann, Andrea Rinaldi, Luciano Cascione, Filippo Spriano, Elena Bernasconi, Francesca Guidetti, Laura Carrassa, Roberta Bordone Pittau, Florent Beaufils, Reto Ritschard, Denise Rageot, Alexander Sele, Barbara Dossena, Francesca M Rossi, Antonella Zucchetto, Monica Taborelli, Valter Gattei, Davide Rossi, Anastasios Stathis, Georg Stussi, Massimo Broggini, Matthias P Wymann, Andreas Wicki, Emanuele Zucca, Vladimir Cmiljanovic, Doriano Fabbro, Francesco Bertoni
PURPOSE: Activation of the PI3K/mTOR signaling pathway is recurrent in different lymphoma types and pharmacological inhibition of the PI3K/mTOR pathway has shown activity in lymphoma patients. Here, we extensively characterized the in vitro and in vivo activity and the mechanism of action of PQR309 (bimiralisib), a novel oral selective dual PI3K/mTOR inhibitor under clinical evaluation, in preclinical lymphoma models. EXPERIMENTAL DESIGN: This study included preclinical in vitro activity screening on a large panel of cell lines, both as single agent and in combination, validation experiments on in vivo models and primary cells, proteomics and gene expression profiling and comparison with other signaling inhibitors...
October 24, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29033940/pi3k%C3%AE-inhibition-enhances-the-antitumor-fitness-of-adoptively-transferred-cd8-t-cells
#20
Jacob S Bowers, Kinga Majchrzak, Michelle H Nelson, Bulent Arman Aksoy, Megan M Wyatt, Aubrey S Smith, Stefanie R Bailey, Lillian R Neal, Jeffrey E Hammerbacher, Chrystal M Paulos
Phosphatidylinositol-3-kinase p110δ (PI3Kδ) inhibition by Idelalisib (CAL-101) in hematological malignancies directly induces apoptosis in cancer cells and disrupts immunological tolerance by depleting regulatory T cells. Yet, little is known about the direct impact of PI3Kδ blockade on effector T cells from CAL-101 therapy. Herein, we demonstrate a direct effect of p110δ inactivation via CAL-101 on murine and human CD8(+) T cells that promotes a strong undifferentiated phenotype (elevated CD62L/CCR7, CD127, and Tcf7)...
2017: Frontiers in Immunology
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