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Selumetinib

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https://www.readbyqxmd.com/read/29216787/mek-inhibitors-under-development-for-treatment-of-non-small-cell-lung-cancer
#1
Chul Kim, Giuseppe Giaccone
The mitogen-activated protein kinase (MAPK) pathway is intimately implicated in the molecular pathogenesis of non-small-cell lung cancer (NSCLC). Aberrant MAPK signaling resulting from the upstream activating mutations converges on mitogen-activated protein kinase kinase 1/2 (MEK1/2), making MEK inhibition an attractive strategy for the treatment of NSCLC. Several MEK inhibitors have demonstrated anticancer activity in patients with NSCLC. Areas covered: In this article, we discuss the biological rationale for the use of MEK inhibitors and summarize the clinical experience with MEK1/2 inhibitors for the treatment of NSCLC, from initial phase I studies to phase II/III studies, both as monotherapy or in combination with other anticancer agents...
December 7, 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/29136201/safety-and-tolerability-of-selumetinib-as-a-monotherapy-or-in-combination-with-docetaxel-as-second-line-therapy-in-japanese-patients-with-advanced-solid-malignancies-or-non-small-cell-lung-cancer
#2
Takashi Seto, Fumihiko Hirai, Hideo Saka, Yoshihito Kogure, Kiyotaka Yoh, Seiji Niho, Kenjiro Fukase, Hitoshi Shimada, Michitaka Sasai, Koichi Fukino
Objective: This Phase I study (NCT01605916) investigated the safety, tolerability and pharmacokinetic profile of selumetinib plus docetaxel as second-line therapy in Japanese patients with locally advanced or metastatic non-small cell lung cancer (NSCLC), or selumetinib monotherapy in Japanese patients with advanced solid malignancies. Methods: All enrolled patients received single-dose selumetinib 25, 50 or 75 mg, followed by a 3-day washout. Combination therapy cohorts then started a 21-day cycle of docetaxel 60 mg/m2 plus selumetinib 25 or 75 mg twice-daily (BID) on Day 1...
November 10, 2017: Japanese Journal of Clinical Oncology
https://www.readbyqxmd.com/read/29100278/somatic-mutations-in-salivary-duct-carcinoma-and-potential-therapeutic-targets
#3
Timothy K Khoo, Bing Yu, Joel A Smith, Angus J Clarke, Peter P Luk, Christina I Selinger, Kate L Mahon, Spiridoula Kraitsek, Carsten Palme, Michael J Boyer, Marcel E Dinger, Mark J Cowley, Sandra A O'Toole, Jonathan R Clark, Ruta Gupta
Background: Salivary duct carcinomas (SDCa) are rare highly aggressive malignancies. Most patients die from distant metastatic disease within three years of diagnosis. There are limited therapeutic options for disseminated disease. Results: 11 cases showed androgen receptor expression and 6 cases showed HER2 amplification. 6 Somatic mutations with additional available targeted therapies were identified: EGFR (p.G721A: Gefitinib), PDGFRA (p.H845Y: Imatinib and Crenolanib), PIK3CA (p...
September 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/29076294/corrigendum-population-pharmacokinetics-of-selumetinib-and-its-metabolite-n-desmethyl-selumetinib-in-adult-patients-with-advanced-solid-tumors-and-children-with-low-grade-gliomas
#4
(no author information available yet)
No abstract text is available yet for this article.
October 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/29055717/development-of-3d-culture-models-of-plexiform-neurofibroma-and-initial-application-for-phenotypic-characterization-and-drug-screening
#5
REVIEW
Janice M Kraniak, Anita Chalasani, Margaret R Wallace, Raymond R Mattingly
Plexiform neurofibromas (PNs), which may be present at birth in up to half of children with type 1 neurofibromatosis (NF1), can cause serious loss of function, such as quadriparesis, and can undergo malignant transformation. Surgery is the first line treatment although the invasive nature of these tumors often prevents complete resection. Recent clinical trials have shown promising success for some drugs, notably selumetinib, an inhibitor of MAP kinase kinase (MEK). We have developed three-dimensional (3D) cell culture models of immortalized cells from NF1 PNs and of control Schwann cells (SCs) that we believe mimic more closely the in vivo condition than conventional two-dimensional (2D) cell culture...
October 18, 2017: Experimental Neurology
https://www.readbyqxmd.com/read/29045535/select-2-a-phase-ii-double-blind-randomised-placebo-controlled-study-to-assess-the-efficacy-of-selumetinib-plus-docetaxel-as-a-second-line-treatment-for-patients-with-advanced-or-metastatic-non-small-cell-lung-cancer
#6
J C Soria, A Fülöp, C Maciel, J R Fischer, G Girotto, S Lago, E Smit, G Ostoros, W E E Eberhardt, P Lishkovska, S Lovick, G Mariani, A McKeown, E Kilgour, P Smith, K Bowen, A Kohlmann, D J Carlile, P A Jänne
Background: Combination of selumetinib plus docetaxel provided clinical benefit in a previous Phase II trial for patients with KRAS-mutant advanced non-small cell lung cancer (NSCLC). The Phase II SELECT-2 trial investigated safety and efficacy of selumetinib plus docetaxel for patients with advanced or metastatic NSCLC. Patients and methods: Patients who had disease progression after first-line anti-cancer therapy were randomised (2:2:1) to selumetinib 75 mg BID plus docetaxel 60 mg/m2 or 75 mg/m2 (SEL+DOC 60; SEL+DOC 75), or placebo plus docetaxel 75 mg/m2 (PBO+DOC 75)...
October 3, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/29040023/dramatic-clinical-and-radiographic-response-to-braf-inhibition-in-a-patient-with-progressive-disseminated-optic-pathway-glioma-refractory-to-mek-inhibition
#7
Abhishek Bavle, Jeremy Jones, Frank Y Lin, Amy Malphrus, Adekunle Adesina, Jack Su
While clinical and radiographic responses to agents targeting the mitogen-activated protein kinases (MAPK) pathway have been repor-ted in pediatric low-grade gliomas (LGG), early phase trials indicate refractoriness to these medications in some of these patients. We report a patient with disseminated LGG with the BRAFV600E mutation, which was refractory to selumetinib, a MEK inhibitor, but subsequently showed immediate clinical and radiographic response to dabrafenib, a BRAF inhibitor, with sustained effect for 9 months prior to clinical progression...
October 17, 2017: Pediatric Hematology and Oncology
https://www.readbyqxmd.com/read/28985960/comparison-of-the-pharmacokinetics-of-the-phase-ii-and-phase-iii-capsule-formulations-of-selumetinib-and-the-effects-of-food-on-exposure-results-from-two-randomized-crossover-trials-in-healthy-male-subjects
#8
Helen Tomkinson, Eileen McBride, Paul Martin, Eleanor Lisbon, Angela W Dymond, Mireille Cantarini, Karen So, David Holt
PURPOSE: Selumetinib (AZD6244, ARRY-142886), an oral, potent, and highly selective mitogen-activated protein kinase 1/2 inhibitor with a short half-life, has shown activity across various tumor types. Before initiation of Phase III trials, the site, scale, and color (hypromellose shell from white [Phase II] to blue [Phase III]) of the selumetinib 25mg capsule manufacture was changed. We present 2 crossover trials evaluating Phase III capsules in healthy subjects. METHODS: The relative bioavailability trial was a Phase I, open-label, randomized, 3-treatment, 4-period, 6-sequence crossover trial in healthy male subjects (aged 18-55 years)...
October 3, 2017: Clinical Therapeutics
https://www.readbyqxmd.com/read/28950288/select-3-a-phase-i-study-of-selumetinib-in-combination-with-platinum-doublet-chemotherapy-for-advanced-nsclc-in-the-first-line-setting
#9
MULTICENTER STUDY
Alastair Greystoke, Nicola Steele, Hendrik-Tobias Arkenau, Fiona Blackhall, Noor Md Haris, Colin R Lindsay, Raffaele Califano, Mark Voskoboynik, Yvonne Summers, Karen So, Dana Ghiorghiu, Angela W Dymond, Stuart Hossack, Ruth Plummer, Emma Dean
BACKGROUND: We investigated selumetinib (AZD6244, ARRY-142886), an oral, potent, and highly selective, allosteric MEK1/2 inhibitor, plus platinum-doublet chemotherapy for patients with advanced/metastatic non-small cell lung cancer. METHODS: In this Phase I, open-label study (NCT01809210), treatment-naïve patients received selumetinib (50, 75, 100 mg BID PO) plus standard doses of gemcitabine or pemetrexed plus cisplatin or carboplatin. Primary objectives were safety, tolerability, and determination of recommended Phase II doses...
September 26, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/28938614/phenformin-enhances-the-therapeutic-effect-of-selumetinib-in-kras-mutant-non-small-cell-lung-cancer-irrespective-of-lkb1-status
#10
Jun Zhang, Sreenivas Nannapaneni, Dongsheng Wang, Fakeng Liu, Xu Wang, Rui Jin, Xiuju Liu, Mohammad Aminur Rahman, Xianghong Peng, Guoqing Qian, Zhuo G Chen, Kwok-Kin Wong, Fadlo R Khuri, Wei Zhou, Dong M Shin
MEK inhibition is potentially valuable in targeting KRAS-mutant non-small cell lung cancer (NSCLC). Here, we analyzed whether concomitant LKB1 mutation alters sensitivity to the MEK inhibitor selumetinib, and whether the metabolism drug phenformin can enhance the therapeutic effect of selumetinib in isogenic cell lines with different LKB1 status. Isogenic pairs of KRAS-mutant NSCLC cell lines A549, H460 and H157, each with wild-type and null LKB1, as well as genetically engineered mouse-derived cell lines 634 (kras(G12D/wt)/p53(-/-)/lkb1(wt/wt)) and t2 (kras(G12D/wt)/p53(-/-)/lkb1(-/-)) were used in vitro to analyze the activities of selumetinib, phenformin and their combination...
August 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28931905/ex-vivo-treatment-of-patient-biopsies-as-a-novel-method-to-assess-colorectal-tumour-response-to-the-mek1-2-inhibitor-selumetinib
#11
Sonia M Novo, Stephen R Wedge, Lesley A Stark
Although an array of new therapeutics has emerged for the treatment of colorectal cancer, their use is significantly impacted by variability in patient response. Better pre-clinical models could substantially improve efficacy as it may allow stratification of patients into the correct treatment regime. Here we explore acute, ex vivo treatment of fresh, surgically resected human colorectal tumour biopsies as a novel pre-clinical model for identifying patient response to specific therapeutics. The MEK1/2 inhibitor, Selumetinib (AZD6244, ARRY-142886) was used as a tool compound...
September 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28921565/the-impact-of-p-glycoprotein-and-breast-cancer-resistance-protein-on-the-brain-pharmacokinetics-and-pharmacodynamics-of-a-panel-of-mek-inhibitors
#12
Mark C de Gooijer, Ping Zhang, Ruud Weijer, Levi C M Buil, Jos H Beijnen, Olaf van Tellingen
Mitogen/extracellular signal-regulated kinase (MEK) inhibitors have been tested in clinical trials for treatment of intracranial neoplasms, including glioblastoma (GBM), but efficacy of these drugs has not yet been demonstrated. The blood-brain barrier (BBB) is a major impediment to adequate delivery of drugs into the brain and may thereby also limit the successful implementation of MEK inhibitors against intracranial malignancies. The BBB is equipped with a range of ATP-dependent efflux transport proteins, of which P-gp (ABCB1) and BCRP (ABCG2) are the two most dominant for drug efflux from the brain...
September 16, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/28916199/erk-and-rock-functionally-interact-in-a-signaling-network-that-is-compensationally-upregulated-in-spinal-muscular-atrophy
#13
Niko Hensel, Svetlana Baskal, Lisa Marie Walter, Hella Brinkmann, Manuela Gernert, Peter Claus
Spinal Muscular Atrophy (SMA) is a motoneuron disease caused by low levels of functional survival of motoneuron protein (SMN). Molecular disease mechanisms downstream of functional SMN loss are still largely unknown. Previous studies suggested an involvement of Rho kinase (ROCK) as well as the extracellular signal-regulated kinases (ERK) pathways in the pathomechanism. Both pathways are bi-directionally linked and inhibit each other. Thus, we hypothesize that both pathways regulate SMA pathophysiology in vivo in a combined manner rather than acting separately...
September 12, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28866094/palbociclib-a-selective-cdk4-6-inhibitor-enhances-the-effect-of-selumetinib-in-ras-driven-non-small-cell-lung-cancer
#14
Jianya Zhou, Shumeng Zhang, Xi Chen, Xianan Zheng, Yinan Yao, Guohua Lu, Jianying Zhou
KRAS is one of the most commonly mutated oncogenes in non-small cell lung cancer (NSCLC). Resistance to MEK inhibitor monotherapy develops through a variety of mechanisms. CDK4 was reported to have a synthetic lethal interaction with KRAS. In this study, we demonstrated the combination effects of the MEK inhibitor selumetinib and the CDK4/6 inhibitor palbociclib in RAS-driven NSCLC. In vitro, cell lines with CDKN2A mutations were insensitive to selumetinib. We used siRNA and pharmacologic inhibition of CDK4 and found that the combination of selumetinib and palbociclib synergistically inhibited RAS-driven NSCLC cases with CDKN2A mutations but not those with wild type CDKN2A...
November 1, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28852199/mutant-jak3-phosphoproteomic-profiling-predicts-synergism-between-jak3-inhibitors-and-mek-bcl2-inhibitors-for-the-treatment-of-t-cell-acute-lymphoblastic-leukemia
#15
S Degryse, C E de Bock, S Demeyer, I Govaerts, S Bornschein, D Verbeke, K Jacobs, S Binos, D A Skerrett-Byrne, H C Murray, N M Verrills, P Van Vlierberghe, J Cools, M D Dun
Mutations in the interleukin-7 receptor (IL7R) or the JAK3 kinase occur frequently in T-cell acute lymphoblastic leukemia (T-ALL) and both are able to drive cellular transformation and the development of T-ALL in mouse models. However, the signal transduction pathways downstream of JAK3 mutations remain poorly characterized. Here, we describe the phosphoproteome downstream of the JAK3(L857Q)/(M511I) activating mutations in transformed Ba/F3 lymphocyte cells. Signaling pathways regulated by JAK3 mutants were assessed following acute inhibition of JAK1/JAK3 using the JAK kinase inhibitors ruxolitinib or tofacitinib...
August 30, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28833380/population-pharmacokinetics-of-the-mek-inhibitor-selumetinib-and-its-active-n-desmethyl-metabolite-data-from-ten-phase-i-trials
#16
Parul Patel, Eleanor Howgate, Paul Martin, David J Carlile, Leon Aarons, Diansong Zhou
AIMS: To characterise the pharmacokinetics (PK) of selumetinib (AZD6244; ARRY-142886), a MEK1/2 inhibitor in clinical development for numerous indications, and its N-desmethyl metabolite in healthy volunteers, and evaluate clinically important covariates. METHODS: A pooledpopulation PK analysis was performed using a non-linear mixed effects approach with plasma concentration data from 346 subjects who received single oral doses of selumetinib 20-75 mg across ten Phase I studies...
August 23, 2017: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28815043/the-mek-inhibitor-selumetinib-complements-ctla-4-blockade-by-reprogramming-the-tumor-immune-microenvironment
#17
Edmund Poon, Stefanie Mullins, Amanda Watkins, Geoffrey S Williams, Jens-Oliver Koopmann, Gianfranco Di Genova, Marie Cumberbatch, Margaret Veldman-Jones, Shaun E Grosskurth, Vasu Sah, Alwin Schuller, Corrine Reimer, Simon J Dovedi, Paul D Smith, Ross Stewart, Robert W Wilkinson
BACKGROUND: T-cell checkpoint blockade and MEK inhibitor combinations are under clinical investigation. Despite progress elucidating the immuno-modulatory effects of MEK inhibitors as standalone therapies, the impact of MEK inhibition on the activity of T-cell checkpoint inhibitors remains incompletely understood. Here we sought to characterize the combined effects of MEK inhibition and anti-CTLA-4 mAb (anti-CTLA-4) therapy, examining effects on both T-cells and tumor microenvironment (TME)...
2017: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/28807001/the-mek-inhibitor-selumetinib-complements-ctla-4-blockade-by-reprogramming-the-tumor-immune-microenvironment
#18
Edmund Poon, Stefanie Mullins, Amanda Watkins, Geoffrey S Williams, Jens-Oliver Koopmann, Gianfranco Di Genova, Marie Cumberbatch, Margaret Veldman-Jones, Shaun E Grosskurth, Vasu Sah, Alwin Schuller, Corrine Reimer, Simon J Dovedi, Paul D Smith, Ross Stewart, Robert W Wilkinson
BACKGROUND: T-cell checkpoint blockade and MEK inhibitor combinations are under clinical investigation. Despite progress elucidating the immuno-modulatory effects of MEK inhibitors as standalone therapies, the impact of MEK inhibition on the activity of T-cell checkpoint inhibitors remains incompletely understood. Here we sought to characterize the combined effects of MEK inhibition and anti-CTLA-4 mAb (anti-CTLA-4) therapy, examining effects on both T-cells and tumor microenvironment (TME)...
August 15, 2017: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/28791489/metalloprotease-dependent-activation-of-egfr-modulates-cd44-cd24-populations-in-triple-negative-breast-cancer-cells-through-the-mek-erk-pathway
#19
Randi Wise, Anna Zolkiewska
PURPOSE: The CD44(+)/CD24(-) cell phenotype is enriched in triple negative breast cancers, is associated with tumor invasive properties, and serves as a cell surface marker profile of breast cancer stem-like cells. Activation of Epidermal Growth Factor Receptor (EGFR) promotes the CD44(+)/CD24(-) phenotype, but the specific signaling pathway downstream of EGFR responsible for this effect is not clear. The purpose of this study was to determine the role of the MEK/ERK pathway in the expansion of CD44(+)/CD24(-) populations in TNBC cells in response to EGFR activation...
November 2017: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/28711086/the-new-paradigm-of-systemic-therapies-for-metastatic-melanoma
#20
REVIEW
Virginia O Volpe, Daniel M Klufas, Upendra Hegde, Jane M Grant-Kels
New treatments for metastatic melanoma work through distinct mechanisms: enhancing the immune response and blocking cellular proliferation. Agents that enhance the immune response include ipilimumab, pembrolizumb, and nivolumab; agents that block cellular proliferation include vemurafenib, dabrafenib, trametinib, cobimetinib, binimetinib, and selumetinib. The translational impact of laboratory discoveries has revolutionized management of metastatic melanoma and enhanced the prognosis of affected patients.
August 2017: Journal of the American Academy of Dermatology
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