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Selumetinib

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https://www.readbyqxmd.com/read/28339824/a-phase-i-trial-of-the-mek-inhibitor-selumetinib-azd6244-in-pediatric-patients-with-recurrent-or-refractory-low-grade-glioma-a-pediatric-brain-tumor-consortium-pbtc-study
#1
Anuradha Banerjee, Regina I Jakacki, Arzu Onar-Thomas, Shengjie Wu, Theodore Nicolaides, Tina Young Poussaint, Jason Fangusaro, Joanna Phillips, Arie Perry, David Turner, Michael Prados, Roger J Packer, Ibrahim Qaddoumi, Sridharan Gururangan, Ian F Pollack, Stewart Goldman, Lawrence A Doyle, Clinton F Stewart, James M Boyett, Larry E Kun, Maryam Fouladi
Background.: Activation of the mitogen-activated protein kinase pathway is important for growth of pediatric low-grade gliomas (LGGs). The aim of this study was to determine the recommended phase II dose (RP2D) and the dose-limiting toxicities (DLTs) of the MEK inhibitor selumetinib in children with progressive LGG. Methods.: Selumetinib was administered orally starting at 33 mg/m2/dose b.i.d., using the modified continual reassessment method. Pharmacokinetic analysis was performed during the first course...
February 28, 2017: Neuro-oncology
https://www.readbyqxmd.com/read/28328340/selumetinib-in-plexiform-neurofibromas
#2
LETTER
(no author information available yet)
No abstract text is available yet for this article.
March 23, 2017: New England Journal of Medicine
https://www.readbyqxmd.com/read/28326681/population-pharmacokinetics-of-selumetinib-and-its-metabolite-n-desmethyl-selumetinib-in-adult-patients-with-advanced-solid-tumors-and-children-with-low-grade-gliomas
#3
Y T Patel, V M Daryani, P Patel, D Zhou, J Fangusaro, D J Carlile, P D Martin, L Aarons, C F Stewart
Selumetinib (AZD6244, ARRY-142886), a mitogen activated protein kinases (MEK1 and 2) inhibitor, has been granted orphan drug designation for differentiated thyroid cancer. The primary aim of this analysis was to characterize the population pharmacokinetics of selumetinib and its active metabolite N-desmethyl-selumetinib in patients with cancer. Concentration-time data from adult and pediatric clinical trials were pooled to develop a population pharmacokinetic model using a sequential approach where selumetinib and N-desmethyl-selumetinib data were modeled separately...
March 22, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28291381/selimetry-a-multicentre-i-131-dosimetry-trial-a-clinical-perspective
#4
Jonathan Wadsley, Rebecca Gregory, Glenn Flux, Kate Newbold, Yong Du, Laura Moss, Andrew Hall, Louise Flanagan, Sarah R Brown
Treatment options for patients with thyroid cancer that is no longer sensitive to iodine therapy are limited. Those treatments which currently exist are associated with significant toxicity. The SELIMETRY trial (EudraCT No 2015-002269-47) aims to investigate the role of the MEK inhibitor Selumetinib in re-sensitising advanced iodine refractory differentiated thyroid cancer to radioiodine therapy. Patients deemed to have sufficient iodine uptake in previously iodine refractory lesions after 4 weeks of Selumetinib therapy will be given an empirical activity of 5...
March 14, 2017: British Journal of Radiology
https://www.readbyqxmd.com/read/28283692/pharmacokinetics-and-pharmacogenetics-of-the-mek1-2-inhibitor-selumetinib-in-asian-and-western-healthy-subjects-a-pooled-analysis
#5
Angela W Dymond, Cathy Elks, Paul Martin, David J Carlile, Gabriella Mariani, Susan Lovick, Yifan Huang, Ulrike Lorch, Helen Brown, Karen So
PURPOSE: Emerging data on selumetinib, a MEK1/2 inhibitor in clinical development, suggest a possible difference in pharmacokinetics (PK) between Japanese and Western patients. This pooled analysis sought to assess the effect of ethnicity on selumetinib exposure in healthy Western and Asian subjects, and to identify any association between genetic variants in the UGT1A1, CYP2C19 and ABCG2 genes and observed differences in selumetinib PK. METHODS: A pooled analysis of data from ten Phase I studies, one in Asian subjects (encompassing Japanese, non-Japanese Asian and Indian Asian subjects) and nine in Western subjects, was conducted...
March 10, 2017: European Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28264648/a-phase-i-dose-escalation-study-of-selumetinib-in-combination-with-docetaxel-or-dacarbazine-in-patients-with-advanced-solid-tumors
#6
Patricia M LoRusso, Jeffrey R Infante, Kevin B Kim, Howard A Burris, Gregory Curt, Ugochi Emeribe, Delyth Clemett, Helen K Tomkinson, Roger B Cohen
BACKGROUND: The RAS/RAF/MEK/ERK pathway is constitutively activated in many cancers. Selumetinib (AZD6244, ARRY-142886) is an oral, potent and highly selective, allosteric MEK1/2 inhibitor with a short half-life that has shown clinical activity as monotherapy in phase I and II studies of advanced cancer. Preclinical data suggest that selumetinib may enhance the activity of chemotherapeutic agents. We assessed the safety, tolerability, and pharmacokinetics (PK) of selumetinib (AZD6244, ARRY-142886) in combination with docetaxel or dacarbazine in patients with advanced solid tumors...
March 6, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28212559/the-selective-mek1-inhibitor-selumetinib-enhances-the-antitumor-activity-of-everolimus-against-renal-cell-carcinoma-in-vitro-and-in-vivo
#7
Yun Zou, Jianfeng Wang, Xuejiao Leng, Jiwei Huang, Wei Xue, Jin Zhang, Yiran Huang
Renal cell carcinoma (RCC) is a urologic malignant cancer and often diagnosed at an advanced stage, which results in high mortality. Targeted therapy may improve the quality of life and survival of patients who are not suitable for nephrectomy. Everolimus, an mTOR inhibitor, is currently used as sequential or second-line therapy for RCC refractory to Sunitinib or sorafenib. However, its efficiency is palliative. In this study, we evaluated whether the antitumor activity of everolimus against RCC is enhanced by Selumetinib, a selective MEK1 inhibitor...
February 14, 2017: Oncotarget
https://www.readbyqxmd.com/read/28179307/selumetinib-inhibits-melanoma-metastasis-to-mouse-liver-via-suppression-of-emt-targeted-genes
#8
Seung-Hee Ryu, Seung-Ho Heo, Eun Young Park, Kyung-Chul Choi, Je-Won Ryu, Seok Ho Lee, Sang-Wook Lee
AIM: We investigated the therapeutic effects of a mitogen-activated protein (MEK) inhibitor, selumetinib, in a hepatic melanoma metastasis model and studied its possible mechanism of action. MATERIALS AND METHODS: Melanoma cell lines were exposed to selumetinib under different experimental conditions. We established a mouse model of liver metastasis and treated mice orally with vehicle or selumetinib and then evaluated metastasis progress. RESULTS: Growth inhibition was observed in melanoma cells as a consequence of G1-phase cell-cycle arrest and the subsequent induction of apoptosis in a dose- and time-dependent manner...
2017: Anticancer Research
https://www.readbyqxmd.com/read/28094260/targeted-therapies-selumetinib-meking-differences-in-nf1
#9
Lisa Hutchinson
No abstract text is available yet for this article.
March 2017: Nature Reviews. Clinical Oncology
https://www.readbyqxmd.com/read/28089105/selumetinib-for-children-with-plexiform-neurofibromas
#10
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
#11
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
#12
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
#13
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...
December 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
#14
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
#15
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
#16
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
#17
RANDOMIZED CONTROLLED TRIAL
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...
March 2017: 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
#18
RANDOMIZED CONTROLLED TRIAL
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...
February 2017: 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
#19
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
#20
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
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