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Mek pd-1

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https://www.readbyqxmd.com/read/27867002/trametinib-plus-4-methylumbelliferone-exhibits-antitumor-effects-by-erk-blockade-and-cd44-downregulation-and-affects-pd1-and-pd-l1-in-malignant-pleural-mesothelioma
#1
Hiroyuki Cho, Seiji Matsumoto, Yoshiko Fujita, Ayumi Kuroda, Toshi Menju, Makoto Sonobe, Nobuyuki Kondo, Ikuko Torii, Takashi Nakano, Primo N Lara, David R Gandara, Hiroshi Date, Seiki Hasegawa
INTRODUCTION: Malignant pleural mesothelioma (MPM) is a highly aggressive malignancy in which the mitogen-activated protein kinase (MAPK) pathway plays a critical role in the regulation of tumorigenesis. Hyaluronan (HA) is a major component of the extracellular matrix, and elevated HA levels, with a concurrent increase in malignant properties, are associated with MPM. METHODS: We evaluated the effects of trametinib, a MAPK kinase enzyme (MEK) inhibitor, and 4-methylumbelliferone (4-MU), an HA synthesis inhibitor, alone and in combination on MPM cells in vitro and in vivo...
November 17, 2016: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/27846317/ras-mitogen-activated-protein-kinase-signal-is-required-for-enhanced-pd-l1-expression-in-human-lung-cancers
#2
Hidetoshi Sumimoto, Atsushi Takano, Koji Teramoto, Yataro Daigo
Ectopic programmed cell death ligand 1 (PD-L1) expression in non-small cell lung cancers (NSCLCs) is related to immune evasion by cancer, and it is a molecular target of immune checkpoint therapies. Although some altered signals in NSCLCs are responsible for ectopic PD-L1 expression, the precise mechanisms remain obscure. Because we found a higher frequency of EGFR/KRAS mutations in NSCLC cell lines with high PD-L1 expression (p < 0.001), we evaluated the relationships between downstream signals and PD-L1 expression, particularly in three KRAS-mutant adenocarcinoma cell lines...
2016: PloS One
https://www.readbyqxmd.com/read/27846054/sequencing-treatment-in-brafv600-mutant-melanoma-anti-pd-1-before-and-after-braf-inhibition
#3
Douglas B Johnson, Eirini Pectasides, Emily Feld, Fei Ye, Shilin Zhao, Romany Johnpulle, Ryan Merritt, David F McDermott, Igor Puzanov, Donald Lawrence, Jeffrey A Sosman, Elizabeth Buchbinder, Ryan J Sullivan
Novel agents targeting immune checkpoint molecules or mutated BRAF are active therapeutic options for patients with BRAF-mutant melanoma. However, the most effective first-line treatment and the optimal sequencing of these agents have not been well characterized. To explore this, we retrospectively assessed 114 patients from 4 centers with advanced, BRAF-mutant melanoma who received anti-programmed cell death-1 (PD-1)/PD-L1 antibodies. We evaluated clinical outcomes, including objective response rate (ORR), overall survival (OS), and progression-free survival (PFS) to initial and subsequent therapies in patients that received anti-PD-1 first (n=56) versus those that received BRAF±MEK inhibitors (BRAFi) first (n=58)...
November 14, 2016: Journal of Immunotherapy
https://www.readbyqxmd.com/read/27833160/photothermal-therapy-improves-the-efficacy-of-a-mek-inhibitor-in-neurofibromatosis-type-1-associated-malignant-peripheral-nerve-sheath-tumors
#4
Elizabeth E Sweeney, Rachel A Burga, Chaoyang Li, Yuan Zhu, Rohan Fernandes
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive tumors with low survival rates and the leading cause of death in neurofibromatosis type 1 (NF1) patients under 40 years old. Surgical resection is the standard of care for MPNSTs, but is often incomplete and can generate loss of function, necessitating the development of novel treatment methods for this patient population. Here, we describe a novel combination therapy comprising MEK inhibition and nanoparticle-based photothermal therapy (PTT) for MPNSTs...
November 11, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27787543/systemic-therapy-for-previously-untreated-advanced-braf-mutated-melanoma-a-systematic-review-and-network-meta-analysis-of-randomized-clinical-trials
#5
Tahira Devji, Oren Levine, Binod Neupane, Joseph Beyene, Feng Xie
Importance: Multiple effective first-line systemic treatment options are available for patients with advanced BRAF-mutated melanoma. A lack of head-to-head randomized clinical trials (RCTs) comparing targeted and immunotherapies leaves uncertainty regarding optimal first-line treatment. Objective: To estimate the relative efficacy and safety of systemic therapies for advanced, treatment-naive, BRAF-mutated melanoma. Data Sources: We searched MEDLINE, Embase, and the Cochrane Central Registry of Controlled Trials for phase 2 or 3 RCTs published up until April 29, 2016...
October 27, 2016: JAMA Oncology
https://www.readbyqxmd.com/read/27710977/the-systemic-management-of-advanced-melanoma-in-2016
#6
Markus V Heppt, Cecilia Dietrich, Saskia A Graf, Thomas Ruzicka, Julia K Tietze, Carola Berking
Melanoma is a common type of skin cancer with a high propensity to metastasize. Tyrosine kinase inhibitors targeting the mitogen-activated protein kinase (MAPK) pathway and immune checkpoint blockade have recently revolutionized the management of unresectable and metastatic disease. However, acquired resistance and primary non-response to therapy require novel treatment strategies and combinations. The purpose of this review is to provide a brief and up-to-date overview on the clinical management and current trial landscape in melanoma...
2016: Oncology Research and Treatment
https://www.readbyqxmd.com/read/27693888/a-phase-i-pharmacokinetic-and-pharmacodynamic-study-of-the-oral-mitogen-activated-protein-kinase-kinase-mek-inhibitor-wx-554-in-patients-with-advanced-solid-tumours
#7
David Jamieson, Melanie J Griffin, Julieann Sludden, Yvette Drew, Nicola Cresti, Karen Swales, Mark Merriman, Rodger Allen, Paul Bevan, Markus Buerkle, Carola Mala, Vicky Coyle, Lisa Rodgers, Emma Dean, Alastair Greystoke, Udai Banerji, Richard H Wilson, T R Jeffery Evans, Alan Anthoney, Malcolm Ranson, Alan V Boddy, Ruth Plummer
PURPOSE: We performed a multi-centre phase I study to assess the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of the orally available small molecule mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor, WX-554, and to determine the optimal biological dose for subsequent trials. EXPERIMENTAL DESIGN: Patients with treatment-refractory, advanced solid tumours, with adequate performance status and organ function were recruited to a dose-escalation study in a standard 3 + 3 design...
September 28, 2016: European Journal of Cancer
https://www.readbyqxmd.com/read/27637745/clinical-outcomes-of-melanoma-brain-metastases-treated-with-stereotactic-radiosurgery-and-anti-pd-1-therapy-anti-ctla-4-therapy-braf-mek-inhibitors-braf-inhibitor-or-conventional-chemotherapy
#8
K A Ahmed, Y A Abuodeh, M I Echevarria, J A Arrington, D G Stallworth, C Hogue, A O Naghavi, S Kim, Y Kim, B G Patel, S Sarangkasiri, P A S Johnstone, S Sahebjam, N I Khushalani, P A Forsyth, L B Harrison, M Yu, A B Etame, J J Caudell
BACKGROUND: The effect of immunologic and targeted agents on intracranial response rates in patients with melanoma brain metastases (MBMs) is not yet clearly understood. This report analyzes outcomes of intact MBMs treated with single-session stereotactic radiosurgery (SRS) and anti-PD-1 therapy, anti-CTLA-4 therapy, BRAF/MEK inhibitors(i), BRAFi, or conventional chemotherapy. PATIENTS AND METHODS: Patients were included if MBMs were treated with single-session SRS within 3 months of receiving systemic therapy...
September 15, 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/27628745/recent-progress-in-mutation-driven-therapy-immunotherapy-and-combination-therapy-for-the-treatment-of-melanoma
#9
Hazem Ihsan Assi, Rita Assi
With increases in our understanding of the human genome and immune system, the treatment armamentarium for melanoma has benefitted from the development and approval of BRAF inhibitors, MEK inhibitors, immune checkpoint modulators via cytotoxic T-lymphocyte antigen-4 blockade, and PD-1 and PD-L1 inhibitors. These advances, however, have raised questions about combination therapy, the optimal sequential use of these agents, the limited assessment of response using traditional metrics, and the optimal selection of the population to be treated...
July 19, 2016: Current Cancer Drug Targets
https://www.readbyqxmd.com/read/27622011/combined-treatment-with-dabrafenib-and-trametinib-with-immune-stimulating-antibodies-for-braf-mutant-melanoma
#10
Blanca Homet Moreno, Stephen Mok, Begonya Comin-Anduix, Siwen Hu-Lieskovan, Antoni Ribas
The combination of targeted therapy with BRAF and MEK inhibitors has become the standard of care in patients with BRAF (V600E) mutant melanoma, but responses are not durable. In addition, the impressive clinical benefits with anti-PD-1 and anti-PD-L1 antibodies (Ab) in patients with heavily pretreated metastatic melanoma and the synergistic effect of dabrafenib, trametinib and anti-PD-1 compared with single therapy alone groups support the idea that combining dabrafenib, trametinib and immunotherapy based on PD-1 blockade could be an interesting approach in the treatment of metastatic melanoma...
July 2016: Oncoimmunology
https://www.readbyqxmd.com/read/27595232/the-mucin-muc1-modulates-the-tumor-immunological-microenvironment-through-engagement-of-the-lectin-siglec-9
#11
Richard Beatson, Virginia Tajadura-Ortega, Daniela Achkova, Gianfranco Picco, Theodora-Dorita Tsourouktsoglou, Sandra Klausing, Matthew Hillier, John Maher, Thomas Noll, Paul R Crocker, Joyce Taylor-Papadimitriou, Joy M Burchell
Siglec-9 is a sialic-acid-binding lectin expressed predominantly on myeloid cells. Aberrant glycosylation occurs in essentially all types of cancers and results in increased sialylation. Thus, when the mucin MUC1 is expressed on cancer cells, it is decorated by multiple short, sialylated O-linked glycans (MUC1-ST). Here we found that this cancer-specific MUC1 glycoform, through engagement of Siglec-9, 'educated' myeloid cells to release factors associated with determination of the tumor microenvironment and disease progression...
November 2016: Nature Immunology
https://www.readbyqxmd.com/read/27583191/indomethacin-induces-increase-in-gastric-epithelial-tight-junction-permeability-via-redistribution-of-occludin-and-activation-of-p38-mapk-in-mkn-28-cells
#12
Meghali Thakre-Nighot, Anthony T Blikslager
Tight Junctions (TJ) create a paracellular barrier that is compromised when nonsteriodal anti-inflammatory drugs (NSAIDs) injure the gastric epithelium, leading to increased permeability. However, the mechanism of NSAID-induced gastric injury is unclear. Here, we examined the effect of indomethacin on barrier function and TJ in gastric MKN-28 cells. In concentration response studies, 500 µm indomethacin induced a significant decrease in transepithelial resistance (TER; 380 vs. 220 Ω·cm(2) for control and indomethacin-treated cells respectively, p < 0...
July 2016: Tissue Barriers
https://www.readbyqxmd.com/read/27573048/current-treatments-for-advanced-melanoma-and-introduction-of-a-promising-novel-gene-therapy-for-melanoma-review
#13
Jae-Rim Heo, Nam-Hyung Kim, Jaejin Cho, Kyung-Chul Choi
Metastatic melanoma is a fatal form of skin cancer that has a tendency to proliferate more rapidly than any other solid tumor. Since 2010, treatment options for metastatic melanoma have been developed including chemotherapies, checkpoint inhibition immunotherapies, e.g., anti‑cytotoxic T‑lymphocyte antigen‑4 (CTLA‑4) and anti‑programmed death‑1 (PD‑1), and molecular-targeted therapies, e.g., BRAF and MEK inhibitors. These treatments have shown not only high response rates yet also side‑effects and limitations...
October 2016: Oncology Reports
https://www.readbyqxmd.com/read/27569556/metastatic-melanoma-insights-into-the-evolution-of-the-treatments-and-future-challenges
#14
Antoine Millet, Anthony R Martin, Cyril Ronco, Stéphane Rocchi, Rachid Benhida
Melanoma is the deadliest form of skin cancer. While associated survival prognosis is good when diagnosed early, it dramatically drops when melanoma progresses into its metastatic form. Prior to 2011, the favored therapies include interleukin-2 and chemotherapies, regardless of their low efficiency and their toxicity. Following key biological findings, two new types of therapy have been approved. First, there are the targeted therapies, which rely on small molecule B-Raf and MEK inhibitors and allow the treatment of patients with B-Raf mutated melanoma...
August 29, 2016: Medicinal Research Reviews
https://www.readbyqxmd.com/read/27461037/the-promise-of-molecularly-targeted-and-immunotherapy-for-advanced-melanoma
#15
REVIEW
Kim Margolin
Advanced melanoma, rarely diagnosed at the time of primary melanoma excision but most often occurring later via lymphatic or hematogenous dissemination, is the cause of death for approximately 10,000 people in the USA each year, with the rate of incidence and death increasing yearly. Its causes are multifactorial and depend in large part on solar ultraviolet damage to DNA as well as underlying genetic predisposition. Cutaneous melanoma is the most common, but other subsets of importance are mucosal and uveal primaries, with different biology and treatment considerations...
September 2016: Current Treatment Options in Oncology
https://www.readbyqxmd.com/read/27447748/fatal-gastrointestinal-toxicity-with-ipilimumab-after-braf-mek-inhibitor-combination-in-a-melanoma-patient-achieving-pathological-complete-response
#16
Maria Gonzalez-Cao, Aram Boada, Cristina Teixidó, María Teresa Fernandez-Figueras, Clara Mayo, Francesc Tresserra, Jean Bustamante, Santiago Viteri, Enrique Puertas, Mariacarmela Santarpia, Aldo Riso, Feliciano Barron, Niki Karachaliou, Rafael Rosell
Approximately 50% of metastatic melanoma patients harbor BRAF mutations. Several treatment options including the combination of BRAF and MEK inhibitors (BRAF/MEKi) and immunotherapy (mainly anti CTLA-4 and anti PD-1 antibodies), have been shown to improve survival in these patients. Although preclinical data support the synergistic effect of both modalities in combination, data confirming the activity and tolerability of these combinations are not yet available in the clinical setting. Herein, we report the case of a melanoma patient treated with sequential BRAF/MEKi (dabrafenib plus trametinib) followed by the anti CTLA-4 antibody ipilimumab who achieved a pathological complete response...
July 18, 2016: Oncotarget
https://www.readbyqxmd.com/read/27429963/resistant-mechanisms-to-braf-inhibitors-in-melanoma
#17
REVIEW
José Luís Manzano, Laura Layos, Cristina Bugés, María de Los Llanos Gil, Laia Vila, Eva Martínez-Balibrea, Anna Martínez-Cardús
Patients with advanced melanoma have traditionally had very poor prognosis. However, since 2011 better understanding of the biology and epidemiology of this disease has revolutionized its treatment, with newer therapies becoming available. These newer therapies can be classified into immunotherapy and targeted therapy. The immunotherapy arsenal includes inhibitors of CTLA4, PD-1 and PDL-1, while targeted therapy focuses on BRAF and MEK. BRAF inhibitors (vemurafenib, dabrafenib) have shown benefit in terms of overall survival (OS) compared to chemotherapy, and their combination with MEK inhibitors has recently been shown to improve progression-free survival (PFS), compared with monotherapy with BRAF inhibitors...
June 2016: Annals of Translational Medicine
https://www.readbyqxmd.com/read/27400655/h4r-activation-utilizes-distinct-signaling-pathways-for-the-production-of-rantes-and-il-13-in-human-mast-cells
#18
Angel Jemima Ebenezer, Prema Arunachalam, Berla Thangam Elden
CONTEXT: The histamine H4 receptor functionally expressed on human mast cells and their signaling pathways for the production of IL-13 and RANTES have never been analyzed side by side in a directly comparable manner. OBJECTIVE: Therefore, the aim of the study was to investigate signaling transduction pathways of H4R via ERK1/2, Akt and NFκB leading to the induction of inflammatory cytokine expression. MATERIALS AND METHODS: In the present study, HMC-1 cells and CBMCs were pretreated individually with H4R antagonist JNJ7777120, H1R antagonist mepyramine and signaling molecule inhibitors PD 98059, LY294002, Bay 117082 followed by stimulation was done with or without histamine or 4-MH...
July 12, 2016: Journal of Receptor and Signal Transduction Research
https://www.readbyqxmd.com/read/27392790/phase-1-study-to-evaluate-the-effect-of-the-mek-inhibitor-trametinib-on-cardiac-repolarization-in-patients-with-solid-tumours
#19
Amita Patnaik, Anthony Tolcher, Kyriakos P Papadopoulos, Murali Beeram, Drew Rasco, Theresa L Werner, John W Bauman, Anita Scheuber, Donna S Cox, Bela R Patel, YanYan Zhou, Mohammed Hamid, Daniel Schramek, Sunil Sharma
PURPOSE: Trametinib is a reversible, selective inhibitor of the mitogen-activated extracellular signal-regulated kinase 1 (MEK1) and 2 (MEK2). Cardiotoxicity (congestive heart failure, decreased heart rate, left ventricular dysfunction, and hypertension) related to trametinib is an infrequent, but serious, adverse event (AE). Prolongation of the QT interval increases the risk of life-threatening cardiac arrhythmia. Thus, the risk of trametinib inducing QT prolongation at putative supratherapeutic exposure was evaluated...
September 2016: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/27367293/diagnosis-and-treatment-of-melanoma-european-consensus-based-interdisciplinary-guideline-update-2016
#20
Claus Garbe, Ketty Peris, Axel Hauschild, Philippe Saiag, Mark Middleton, Lars Bastholt, Jean-Jacques Grob, Josep Malvehy, Julia Newton-Bishop, Alexander J Stratigos, Hubert Pehamberger, Alexander M Eggermont
Cutaneous melanoma (CM) is potentially the most dangerous form of skin tumour and causes 90% of skin cancer mortality. A unique collaboration of multi-disciplinary experts from the European Dermatology Forum, the European Association of Dermato-Oncology and the European Organisation of Research and Treatment of Cancer was formed to make recommendations on CM diagnosis and treatment, based on systematic literature reviews and the experts' experience. Diagnosis is made clinically using dermoscopy and staging is based upon the AJCC system...
August 2016: European Journal of Cancer
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