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Selumetinib

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https://www.readbyqxmd.com/read/28094260/targeted-therapies-selumetinib-meking-differences-in-nf1
#1
Lisa Hutchinson
No abstract text is available yet for this article.
January 17, 2017: Nature Reviews. Clinical Oncology
https://www.readbyqxmd.com/read/28089105/selumetinib-for-children-with-plexiform-neurofibromas
#2
Talha Khan Burki
No abstract text is available yet for this article.
January 6, 2017: Lancet Oncology
https://www.readbyqxmd.com/read/28070119/ocd-like-behavior-is-caused-by-dysfunction-of-thalamo-amygdala-circuits-and-upregulated-trkb-erk-mapk-signaling-as-a-result-of-spred2-deficiency
#3
M Ullrich, M Weber, A M Post, S Popp, J Grein, M Zechner, H Guerrero González, A Kreis, A G Schmitt, N Üçeyler, K-P Lesch, K Schuh
Obsessive-compulsive disorder (OCD) is a common neuropsychiatric disease affecting about 2% of the general population. It is characterized by persistent intrusive thoughts and repetitive ritualized behaviors. While gene variations, malfunction of cortico-striato-thalamo-cortical (CSTC) circuits, and dysregulated synaptic transmission have been implicated in the pathogenesis of OCD, the underlying mechanisms remain largely unknown. Here we show that OCD-like behavior in mice is caused by deficiency of SPRED2, a protein expressed in various brain regions and a potent inhibitor of Ras/ERK-MAPK signaling...
January 10, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/28053239/microrna-378-reduces-mesangial-hypertrophy-and-kidney-tubular-fibrosis-via-mapk-signaling
#4
Bo Wang, Kevin Yao, Andrea F Wise, Ricky Lau, Hsin-Hui Shen, Greg H Tesch, Sharon D Ricardo
AIMS: To determine the regulatory role of a novel miRNA, miR-378, in the development of fibrosis through repression of the MAPK1 (ERK2) pathway. METHODS: miR-378 and fibrotic gene expression was examined in streptozotocin (STZ)-induced diabetic mice at 18 weeks or in unilateral ureteral obstruction (UUO) mice at 7 days. miR-378 transfection of proximal tubular epithelial cells, NRK52E, and mesangial cells was assessed with/without endogenous miR-378 knockdown using the locked nucleic acid (LNA) inhibitor...
January 4, 2017: Clinical Science (1979-)
https://www.readbyqxmd.com/read/28029918/activity-of-selumetinib-in-neurofibromatosis-type-1-related-plexiform-neurofibromas
#5
Eva Dombi, Andrea Baldwin, Leigh J Marcus, Michael J Fisher, Brian Weiss, AeRang Kim, Patricia Whitcomb, Staci Martin, Lindsey E Aschbacher-Smith, Tilat A Rizvi, Jianqiang Wu, Rachel Ershler, Pamela Wolters, Janet Therrien, John Glod, Jean B Belasco, Elizabeth Schorry, Alessandra Brofferio, Amy J Starosta, Andrea Gillespie, Austin L Doyle, Nancy Ratner, Brigitte C Widemann
Background Effective medical therapies are lacking for the treatment of neurofibromatosis type 1-related plexiform neurofibromas, which are characterized by elevated RAS-mitogen-activated protein kinase (MAPK) signaling. Methods We conducted a phase 1 trial of selumetinib (AZD6244 or ARRY-142886), an oral selective inhibitor of MAPK kinase (MEK) 1 and 2, in children who had neurofibromatosis type 1 and inoperable plexiform neurofibromas to determine the maximum tolerated dose and to evaluate plasma pharmacokinetics...
29, 2016: New England Journal of Medicine
https://www.readbyqxmd.com/read/28019010/pharmacokinetics-of-a-single-oral-dose-of-the-mek1-2-inhibitor-selumetinib-in-subjects-with-end-stage-renal-disease-or-varying-degrees-of-hepatic-impairment-compared-with-healthy-subjects
#6
Angela W Dymond, Paul Martin, Karen So, Yifan Huang, Paul Severin, Victoria Holmes, Gabriella Mariani, Thomas Marbury
Two phase I open-label studies were conducted to investigate the pharmacokinetics (PK), safety, and tolerability of single oral doses of selumetinib in subjects with end-stage renal disease (ESRD) undergoing hemodialysis and subjects with varying degrees of hepatic impairment; both studies included a matched control group comprised of healthy individuals. In the renal impairment study, subjects received single doses of selumetinib 50 mg; those with ESRD received selumetinib before and after dialysis (with a between-treatment washout period of ≥7 days)...
December 26, 2016: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/27978579/effect-of-selumetinib-and-mk-2206-vs-oxaliplatin-and-fluorouracil-in-patients-with-metastatic-pancreatic-cancer-after-prior-therapy-swog-s1115-study-randomized-clinical-trial
#7
Vincent Chung, Shannon McDonough, Philip A Philip, Dana Cardin, Andrea Wang-Gillam, Laifong Hui, Mohamedtaki A Tejani, Tara E Seery, Irene A Dy, Tareq Al Baghdadi, Andrew E Hendifar, L Austin Doyle, Andrew M Lowy, Katherine A Guthrie, Charles D Blanke, Howard S Hochster
Importance: KRAS mutations are common in pancreatic cancer, but directly targeting the KRAS protein has thus far been unsuccessful. The aim of this trial was to block the MEK and PI3K/AKT pathways downstream of the KRAS protein as an alternate treatment strategy to slow cancer growth and prolong survival. This was the first cooperative group trial to evaluate this strategy using molecularly targeted oral combination therapy for the treatment of chemotherapy-refractory pancreatic cancer...
December 15, 2016: JAMA Oncology
https://www.readbyqxmd.com/read/27939899/high-content-imaging-platform-for-profiling-intracellular-signaling-network-activity-in-living-cells
#8
Dmitry Kuchenov, Vibor Laketa, Frank Stein, Florian Salopiata, Ursula Klingmüller, Carsten Schultz
Essential characteristics of cellular signaling networks include a complex interconnected architecture and temporal dynamics of protein activity. The latter can be monitored by Förster resonance energy transfer (FRET) biosensors at a single-live-cell level with high temporal resolution. However, these experiments are typically limited to the use of a couple of FRET biosensors. Here, we describe a FRET-based multi-parameter imaging platform (FMIP) that allows simultaneous high-throughput monitoring of multiple signaling pathways...
December 22, 2016: Cell Chemical Biology
https://www.readbyqxmd.com/read/27921276/relationship-between-physician-adjudicated-adverse-events-and-patient-reported-health-related-quality-of-life-in-a-phase-ii-clinical-trial-nct01143402-of-patients-with-metastatic-uveal-melanoma
#9
Thomas M Atkinson, Jennifer L Hay, Alexander Shoushtari, Yuelin Li, Daniel J Paucar, Sloane C Smith, Ragini R Kudchadkar, Austin Doyle, Jeffrey A Sosman, Jorge Fernando Quevedo, Mohammed M Milhem, Anthony M Joshua, Gerald P Linette, Thomas F Gajewski, Jose Lutzky, David H Lawson, Christopher D Lao, Patrick J Flynn, Mark R Albertini, Takami Sato, Karl Lewis, Brian Marr, David H Abramson, Mark Andrew Dickson, Gary K Schwartz, Richard D Carvajal
PURPOSE: Clinical trials commonly use physician-adjudicated adverse event (AE) assessment via the common terminology criteria for adverse events (CTCAE) for decision-making. Patient-reported health-related quality of life (HRQoL) data are becoming more frequent in oncology; however, the relationship between physician-adjudicated AE assessment and HRQoL is understudied. METHODS: Data from a phase II trial (clinicaltrials.gov identifier: NCT01143402) where patients with metastatic uveal melanoma were randomized to receive selumetinib, an oral MEK inhibitor, or chemotherapy were analyzed...
December 5, 2016: Journal of Cancer Research and Clinical Oncology
https://www.readbyqxmd.com/read/27889832/effects-of-cytochrome-p450-cyp3a4-and-cyp2c19-inhibition-and-induction-on-the-exposure-of-selumetinib-a-mek1-2-inhibitor-in-healthy-subjects-results-from-two-clinical-trials
#10
Angela W Dymond, Karen So, Paul Martin, Yifan Huang, Paul Severin, David Mathews, Eleanor Lisbon, Gabriella Mariani
PURPOSE: Two phase I, open-label trials in healthy subjects assessed whether co-administration with CYP3A4/CYP2C19 inhibitors, itraconazole/fluconazole (study A), or CYP3A4 inducer, rifampicin (study B), affects the exposure, safety/tolerability and pharmacokinetics of selumetinib and its metabolite N-desmethyl selumetinib. METHODS: In study A (n = 26), subjects received a single dose of selumetinib 25 mg and, after 4 days of washout, were randomized to treatment 1 (itraconazole 200 mg twice daily on days 1-11) or treatment 2 (fluconazole 400 mg on day 1 then 200 mg/day on days 2-11) plus co-administration of single-dose selumetinib 25 mg on day 8 (selumetinib staggered 4 h after itraconazole/fluconazole dose); Twenty-one days after discharge/washout, subjects received the alternate treatment...
November 26, 2016: European Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/27822414/differences-in-mek-inhibitor-efficacy-in-molecularly-characterized-low-grade-serous-ovarian-cancer-cell-lines
#11
Marta Llauradó Fernández, Gabriel E DiMattia, Amy Dawson, Sylvia Bamford, Shawn Anderson, Bryan T Hennessy, Michael S Anglesio, Trevor G Shepherd, Clara Salamanca, Josh Hoenisch, Anna Tinker, David G Huntsman, Mark S Carey
Advanced or recurrent low-grade serous ovarian cancers (LGSC) are resistant to conventional systemic treatments. LGSC carry mutations in RAS or RAF, leading to several clinical trials evaluating MEK inhibitors (MEKi). As LGSC cell lines and xenografts have been difficult to establish, little is known about the efficacy and on-target activity of MEKi treatment in this disease. We compared four different MEKi (trametinib, selumetinib, binimetinib and refametinib) in novel LGSC patient-derived cell lines. Molecular characterization of these cells included copy-number variation and hotspot mutational analysis...
2016: American Journal of Cancer Research
https://www.readbyqxmd.com/read/27813079/the-plasma-membrane-ca-2-pump-pmca4b-inhibits-the-migratory-and-metastatic-activity-of-braf-mutant-melanoma-cells
#12
L Hegedus, T Garay, E Molnar, K Varga, A Bilecz, S Torok, R Padanyi, K Paszty, M Wolf, M Grusch, E Kallay, B Dome, W Berger, B Hegedus, A Enyedi
Oncogenic mutations of BRAF lead to constitutive ERK activity that supports melanoma cell growth and survival. While Ca(2+) signaling is a well-known regulator of tumor progression, the crosstalk between Ca(2+) signaling and the Ras-BRAF-MEK-ERK pathway is much less explored. Here we show that in BRAF mutant melanoma cells the abundance of the plasma membrane Ca(2+) ATPase isoform 4b (PMCA4b, ATP2B4) is low at baseline but markedly elevated by treatment with the mutant BRAF specific inhibitor vemurafenib. In line with these findings gene expression microarray data also shows decreased PMCA4b expression in cutaneous melanoma when compared to benign nevi...
November 4, 2016: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/27769200/selumetinib-suppresses-cell-proliferation-migration-and-trigger-apoptosis-g1-arrest-in-triple-negative-breast-cancer-cells
#13
Yan Zhou, Shuchen Lin, Kuo-Fu Tseng, Kun Han, Yaling Wang, Zhi-Hua Gan, Da-Liu Min, Hai-Yan Hu
BACKGROUND: Triple-negative breast cancer (TNBC) has aggressive progression with poor prognosis and ineffective treatments. Selumetinib is an allosteric, ATP-noncompetitive inhibitor of MEK1/2, which has benn known as effective antineoplastic drugs for several malignant tumors. We hypothesized that Selumetinib might be potential drug for TNBC and explore the mechanism. METHODS: After treated with Selumetinib, the viability and mobility of HCC1937 and MDA-MB-231 were detected by MTT, tunnel, wound-healing assay, transwell assay and FCM methods...
October 21, 2016: BMC Cancer
https://www.readbyqxmd.com/read/27751676/metabolism-excretion-and-pharmacokinetics-of-selumetinib-an-mek1-2-inhibitor-in-healthy-adult-male-subjects
#14
Angela W Dymond, Colin Howes, Christine Pattison, Karen So, Gabriella Mariani, Mark Savage, Stuart Mair, Gill Ford, Paul Martin
PURPOSE: Selumetinib (AZD6244, ARRY-142886), an oral mitogen activated kinase 1/2 inhibitor, is in clinical development for the treatment of a variety of different tumor types. Herein, we report a study that determined the distribution, metabolism, and excretion of selumetinib in healthy male volunteers. METHODS: In this open-label, single-center, Phase I clinical trial, 6 subjects received a single 75-mg dose of [(14)C]-selumetinib. Blood and excreta samples were collected for pharmacokinetic and radiometric analyses...
October 14, 2016: Clinical Therapeutics
https://www.readbyqxmd.com/read/27681866/a-phase-ib-study-of-selumetinib-azd6244-arry-142886-in-combination-with-sorafenib-in-advanced-hepatocellular-carcinoma-hcc
#15
W M Tai, W P Yong, C Lim, L S Low, C K Tham, T S Koh, Q S Ng, W W Wang, L Z Wang, S Hartano, C H Thng, H Huynh, K T Lim, H C Toh, B C Goh, S P Choo
BACKGROUND: Treatment with sorafenib, although associated with inhibition of tumour growth and angiogenesis in in vivo studies, leads to up-regulation of pERK. The addition of MEK inhibition could potentially abrogate this effect and potentiate anti-tumour activity. This phase I study investigated the maximum tolerated dose (MTD), safety, tolerability, pharmacokinetics (PK) and biomarker correlates of selumetinib combined with sorafenib in patients with advanced hepatocellular carcinoma (HCC)...
December 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/27670699/identification-of-tra2b-dnah5-fusion-as-a-novel-oncogenic-driver-in-human-lung-squamous-cell-carcinoma
#16
Fei Li, Zhaoyuan Fang, Jian Zhang, Chen Li, Hongyan Liu, Jufeng Xia, Hongwen Zhu, Chenchen Guo, Zhen Qin, Fuming Li, Xiangkun Han, Yuetong Wang, Yan Feng, Ye Wang, Wenjing Zhang, Zuoyun Wang, Yujuan Jin, Yihua Sun, Wenyi Wei, Rong Zeng, Haiquan Chen, Hongbin Ji
Lung squamous cell carcinoma (SCC) is one of the major subtypes of lung cancer. Our current knowledge of oncogenic drivers in this specific subtype of lung cancer is largely limited compared with lung adenocarcinoma (ADC). Through exon array analyses, molecular analyses and functional studies, we here identify the TRA2B-DNAH5 fusion as a novel oncogenic driver in lung SCC. We found that this gene fusion occurs exclusively in lung SCC (3.1%, 5/163), but not in lung ADC (0/119). Through mechanistic studies, we further revealed that this TRA2B-DNAH5 fusion promotes lung SCC malignant progression through regulating a SIRT6-ERK1/2-MMP1 signaling axis...
October 2016: Cell Research
https://www.readbyqxmd.com/read/27669459/sustained-erk-inhibition-maximizes-responses-of-brafv600e-thyroid-cancers-to-radioiodine
#17
James Nagarajah, Mina Le, Jeffrey A Knauf, Giuseppe Ferrandino, Cristina Montero-Conde, Nagavarakishore Pillarsetty, Alexander Bolaender, Christopher Irwin, Gnana Prakasam Krishnamoorthy, Mahesh Saqcena, Steven M Larson, Alan L Ho, Venkatraman Seshan, Nobuya Ishii, Nancy Carrasco, Neal Rosen, Wolfgang A Weber, James A Fagin
Radioiodide (RAI) therapy of thyroid cancer exploits the relatively selective ability of thyroid cells to transport and accumulate iodide. Iodide uptake requires expression of critical genes that are involved in various steps of thyroid hormone biosynthesis. ERK signaling, which is markedly increased in thyroid cancer cells driven by oncogenic BRAF, represses the genetic program that enables iodide transport. Here, we determined that a critical threshold for inhibition of MAPK signaling is required to optimally restore expression of thyroid differentiation genes in thyroid cells and in mice with BrafV600E-induced thyroid cancer...
November 1, 2016: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/27636997/synthetic-lethal-interaction-of-cetuximab-with-mek1-2-inhibition-in-nras-mutant-metastatic-colorectal-cancer
#18
Bernardo Queralt, Elisabet Cuyàs, Joaquim Bosch-Barrera, Anna Massaguer, Rafael de Llorens, Begoña Martin-Castillo, Joan Brunet, Ramon Salazar, Javier A Menendez
KRAS mutations are an established predictor of lack of response to EGFR-targeted therapies in patients with metastatic colorectal cancer (mCRC). However, little is known about the role of the rarer NRAS mutations as a mechanism of primary resistance to the anti-EGFR monoclonal antibody cetuximab in wild-type KRAS mCRC. Using isogenic mCRC cells with a heterozygous knock-in of the NRAS activating mutation Q61K, we aimed to elucidate the mechanism(s) by which mutant NRAS blocks cetuximab from inhibiting mCRC growth...
September 12, 2016: Oncotarget
https://www.readbyqxmd.com/read/27599525/selumetinib-attenuate-skeletal-muscle-wasting-in-murine-cachexia-model-through-erk-inhibition-and-akt-activation
#19
Yang Quan-Jun, Huo Yan, Han Yong-Long, Wan Li-Li, Li Jie, Huang Jin-Lu, Lu Jin, Chen Peng-Guo, Gan Run, Guo Cheng
Cancer cachexia is a multifactorial syndrome affecting the skeletal muscle. Previous clinical trials showed MEK inhibitor selumetinib treatment resulted in skeletal muscle anabolism. However, it is conflicting that MAPK/ERK pathway control mass of skeletal muscle. The present study investigated the therapeutic effect and mechanisms of selumetinib in amelioration of cancer cachexia. The classical cancer cachexia model was established via transplantation of CT26 colon adenocarcinoma into BALB/c mice. The effect of selumetinib on body weight, tumor growth, skeletal muscle, food intake, serum proinflammatory cytokines, E3 ligases and MEK/ERK-related pathways was analyzed...
September 6, 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27588400/mek-inhibition-is-a-promising-therapeutic-strategy-for-mll-rearranged-infant-acute-lymphoblastic-leukemia-patients-carrying-ras-mutations
#20
Mark Kerstjens, Emma M C Driessen, Merel Willekes, Sandra S Pinhanços, Pauline Schneider, Rob Pieters, Ronald W Stam
Acute lymphoblastic leukemia (ALL) in infants is an aggressive malignancy with a poor clinical outcome, and is characterized by translocations of the Mixed Lineage Leukemia (MLL) gene. Previously, we identified RAS mutations in 14-24% of infant ALL patients, and showed that the presence of a RAS mutation decreased the survival chances even further. We hypothesized that targeting the RAS signaling pathway could be a therapeutic strategy for RAS-mutant infant ALL patients. Here we show that the MEK inhibitors Trametinib, Selumetinib and MEK162 severely impair primary RAS-mutant MLL-rearranged infant ALL cells in vitro...
August 31, 2016: Oncotarget
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