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Selumetinib

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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
#1
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
#2
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
#3
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
#4
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
#5
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
#6
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
#7
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)...
September 28, 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
#8
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
#9
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
#10
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
#11
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
#12
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
https://www.readbyqxmd.com/read/27572939/gli-inhibitor-gant61-kills-melanoma-cells-and-acts-in-synergy-with-obatoclax
#13
Kateřina Vlčková, Jiri Réda, Lubica Ondrušová, Mohammad Krayem, Ghanem Ghanem, Jiri Vachtenheim
MEK kinase inhibitors (trametinib and selumetinib) or kinase inhibitors directed against mutated BRAF(V600E) (vemurafenib and dabrafenib) have initial encouraging effects in the treatment of melanoma but acquired resistance appears almost invariably after some months. Studies revealed mutually exclusive NRAS and BRAF activating mutations driving the MAPK/ERK pathway among human melanomas. Although combination therapy exerts significantly better antitumor cell efficacy, complete remission is rarely achieved...
September 2016: International Journal of Oncology
https://www.readbyqxmd.com/read/27523799/determination-of-selumetinib-n-desmethyl-selumetinib-and-selumetinib-amide-in-human-biological-samples-by-lc-ms-ms
#14
Paul Severin, Christopher Bailey, Meng Chen, Ashley Fisher, Victoria Holmes
AIM: Selumetinib is an inhibitor of MEK1/2 in Phase III development that has activity in multiple tumor types. Validated bioanalytical methods were required to quantitate selumetinib and its N-desmethyl and amide metabolites in a variety of human biological matrices. Methodology & results: LC-MS/MS assays were developed and validated that demonstrated acceptable precision, accuracy and selectivity for selumetinib and the two metabolites in human plasma, urine, blood dialysate and plasma ultrafiltrate...
September 2016: Bioanalysis
https://www.readbyqxmd.com/read/27494873/combinatorial-therapeutic-targeting-of-bmp2-and-mek-erk-pathways-in-nf1-associated-malignant-peripheral-nerve-sheath-tumors
#15
Sidra Ahsan, Yubin Ge, Michael A Tainsky
The clinical management of malignant peripheral nerve sheath tumors (MPNSTs) is challenging not only due to its aggressive and invasive nature, but also limited therapeutic options. Using gene expression profiling, our lab identified BMP2-SMAD1/5/8 pathway as a potential therapeutic target for treating MPNSTs. In this study, we explored the therapeutic impact of targeting BMP2-SMAD1/5/8 pathway in conjunction with RAS-MEK-ERK signaling, which is constitutively activated in MPNSTs. Our results indicated that single agent treatment with LDN-193189, a BMP2 Type I receptor inhibitor, did not affect the growth and survival of MPNST cells at biochemically relevant inhibitory concentrations...
August 3, 2016: Oncotarget
https://www.readbyqxmd.com/read/27469379/targeting-the-mitogen-activated-protein-kinase-pathway-in-low-grade-serous-carcinoma-of-the-ovary
#16
Jennifer McLachlan, Martin Gore, Susana Banerjee
Until recently, there has been little change in the management of epithelial ovarian cancer with the majority of women receiving identical systemic therapy, regardless of histological subtype. The heterogeneity of epithelial ovarian cancer is now well established, with distinct subtypes characterized by specific molecular alterations and patterns of clinical behavior. Low-grade serous carcinoma is a rare subtype associated with an indolent biological behavior and inherent resistance to chemotherapy. The mitogen-activated protein kinase pathway plays a prominent role in the pathogenesis of low-grade serous carcinoma, and provides an attractive target for novel therapeutic agents...
August 2016: Pharmacogenomics
https://www.readbyqxmd.com/read/27467210/selumetinib-in-the-treatment-of-non-small-cell-lung-cancer
#17
Reyes Bernabé, Ana Patrao, Louise Carter, Fiona Blackhall, Emma Dean
The RAS-RAF-MEK-ERK pathway regulates processes involved in the proliferation and survival of cells. KRAS mutations, prevalent in approximately 30% of patients with non-small-cell lung cancer (NSCLC), result in constitutive activation of the pathway. Selumetinib (AZD6244, ARRY-142886) is a potent and selective inhibitor of MEK1/2 which has demonstrated significant efficacy in combination with docetaxel in patients with KRAS mutant pretreated advanced NSCLC. Several trials in combination with other chemotherapy and targeted therapy regimens in lung cancer are ongoing...
July 28, 2016: Future Oncology
https://www.readbyqxmd.com/read/27448918/autophagy-regulates-selumetinib-azd6244-induced-apoptosis-in-colorectal-cancer-cells
#18
Silvina Grasso, Gustavo J S Pereira, Caroline Palmeira-Dos-Santos, Andrana K Calgarotto, Isabel Martínez-Lacaci, Jose Antonio Ferragut, Soraya S Smaili, Claudia Bincoletto
OBJECTIVE: As Selumetinib is a MEK1/2 inhibitor that has gained interest as an anti-tumor agent, the present study was designed to investigate autophagy involvement on Selumetinib-induced apoptosis in colorectal cancer (CRC) cells. METHODS: CRC cells death and cycle studies were assessed by AnnexinV-FITC and PI staining, respectively. Autophagy flux was analysed by Western Blot (LC3II and p62 protein levels) and retroviral infection of SW480 cells for siBecn1 RNA interference experiments...
October 21, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27438013/selumetinib-an-oral-anti-neoplastic-drug-may-attenuate-cardiac-hypertrophy-via-targeting-the-erk-pathway
#19
Chen Li, Zhongxiu Chen, Hao Yang, Fangbo Luo, Lihong Chen, Huawei Cai, Yajiao Li, Guiying You, Dan Long, Shengfu Li, Qiuping Zhang, Li Rao
AIMS: Although extracellular-regulated kinases (ERK) are a well-known central mediator in cardiac hypertrophy, no clinically available ERK antagonist has been tested for preventing cardiac hypertrophy. Selumetinib is a novel oral MEK inhibitor that is currently under Phase II and Phase III clinical investigation for advanced solid tumors. In this study, we investigated whether Selumetinib could inhibit the aberrant ERK activation of the heart in response to stress as well as prevent cardiac hypertrophy...
2016: PloS One
https://www.readbyqxmd.com/read/27422710/phosphoproteomics-reveals-mapk-inhibitors-enhance-met-and-egfr-driven-akt-signaling-in-kras-mutant-lung-cancer
#20
Jae-Young Kim, Eric A Welsh, Bin Fang, Yun Bai, Fumi Kinose, Steven A Eschrich, John M Koomen, Eric B Haura
: Pathway inhibition of the RAS-driven MAPK pathway using small-molecule kinase inhibitors has been a key focus for treating cancers driven by oncogenic RAS, yet significant clinical responses are lacking. Feedback reactivation of ERK driven by drug-induced RAF activity has been suggested as one of the major drug resistance mechanisms, especially in the context of oncogenic RAS. To determine whether additional adaptive resistance mechanisms may coexist, we characterized global phosphoproteomic changes after MEK inhibitor selumetinib (AZD6244) treatment in KRAS-mutant A427 and A549 lung adenocarcinoma cell lines employing mass spectrometry-based phosphoproteomics...
October 2016: Molecular Cancer Research: MCR
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