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Selumetinib

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https://www.readbyqxmd.com/read/29849102/combinatorial-drug-testing-in-3d-microtumors-derived-from-gbm-patient-derived-xenografts-reveals-cytotoxic-synergy-in-pharmacokinomics-informed-pathway-interactions
#1
Ashley N Gilbert, Joshua C Anderson, Christine W Duarte, Rachael S Shevin, Catherine P Langford, Raj Singh, G Yancey Gillespie, Christopher D Willey
Glioblastoma multiforme (GBM), the most common form of primary malignant brain cancer in adults, is a devastating disease for which effective treatment has remained elusive for over 75 years. One reason for the minimal progress during this time is the lack of accurate preclinical models to represent the patient's tumor's in vivo environment, causing a disconnect in drug therapy effectiveness between the laboratory and clinic. While patient-derived xenografts (PDX's or xenolines) are excellent human tumor representations, they are not amenable to high throughput testing...
May 30, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29774094/selumetinib-based-therapy-in-uveal-melanoma-patient-derived-xenografts
#2
Didier Decaudin, Rania El Botty, Béré Diallo, Gerald Massonnet, Justine Fleury, Adnan Naguez, Chloé Raymondie, Emma Davies, Aaron Smith, Joanne Wilson, Colin Howes, Paul D Smith, Nathalie Cassoux, Sophie Piperno-Neumann, Sergio Roman-Roman, Fariba Némati
The prognosis of metastatic uveal melanoma (UM) is among the worst of all human cancers. The identification of near-ubiquitous GNAQ/GNA11 mutations and the activation of MAPK signaling in UM have raised hopes of more effective, targeted therapies, based on MEK inhibition, for example. We evaluated the potential of drug combinations to increase the efficacy of the MEK inhibitor selumetinib (AZD6244, ARRY-142886), in UM cell lines and Patient-Derived Xenografts. We first evaluated the combination of selumetinib and DTIC...
April 24, 2018: Oncotarget
https://www.readbyqxmd.com/read/29762469/individualised-multimodal-treatment-strategies-for-anaplastic-and-poorly-differentiated-thyroid-cancer
#3
Sabine Wächter, Annette Wunderlich, Silvia Roth, Ioannis Mintziras, Elisabeth Maurer, Sebastian Hoffmann, Frederik A Verburg, Sebastian A Fellinger, Katharina Holzer, Detlef K Bartsch, Pietro Di Fazio
The prognosis of anaplastic (ATC) and poorly differentiated thyroid cancer (PDTC) is poor, due to their radioiodine refractoriness (RAI-R), high metastatic potential and current lack of effective treatment strategies. We aimed to examine the efficacy of the tyrosine kinase inhibitors (TKIs) sorafenib and selumetinib and the histone deacetylase inhibitor (HDACI) panobinostat in patient-derived tumor tissue (PDTT) of ATCs/PDTCs, the expression of sodium iodide symporter ( NIS ) and radioiodine up-take (RAI-U)...
May 15, 2018: Journal of Clinical Medicine
https://www.readbyqxmd.com/read/29739364/pan-raf-and-mek-vertical-inhibition-enhances-therapeutic-response-in-non-v600-braf-mutant-cells
#4
Eszter Molnár, Dominika Rittler, Marcell Baranyi, Michael Grusch, Walter Berger, Balázs Döme, József Tóvári, Clemens Aigner, József Tímár, Tamás Garay, Balázs Hegedűs
BACKGROUND: Currently, there are no available targeted therapy options for non-V600 BRAF mutated tumors. The aim of this study was to investigate the effects of RAF and MEK concurrent inhibition on tumor growth, migration, signaling and apoptosis induction in preclinical models of non-V600 BRAF mutant tumor cell lines. METHODS: Six BRAF mutated human tumor cell lines CRL5885 (G466 V), WM3629 (D594G), WM3670 (G469E), MDAMB231 (G464 V), CRL5922 (L597 V) and A375 (V600E as control) were investigated...
May 8, 2018: BMC Cancer
https://www.readbyqxmd.com/read/29719377/attenuation-of-everolimus-induced-cytotoxicity-by-a-protective-autophagic-pathway-involving-erk-activation-in-renal-cell-carcinoma-cells
#5
Yizhou Zeng, Xiaofang Tian, Quan Wang, Weiyang He, Jing Fan, Xin Gou
Aim: The mammalian target of rapamycin (mTOR) pathway is a critical target for cancer treatment and the mTOR inhibitor everolimus (RAD001) has been approved for treatment of renal cell carcinoma (RCC). However, the limited efficacy of RAD001 has led to the development of drug resistance. Autophagy is closely related to cell survival and death, which may be activated under RAD001 stimulation. The aim of the present study was to identify the underlying mechanisms of RAD001 resistance in RCC cells through cytoprotective autophagy involving activation of the extracellular signal-regulated kinase (ERK) pathway...
2018: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/29670612/-n-formyl-peptide-receptors-induce-radical-oxygen-production-in-fibroblasts-derived-from-systemic-sclerosis-by-interacting-with-a-cleaved-form-of-urokinase-receptor
#6
Filomena Napolitano, Francesca Wanda Rossi, Ada Pesapane, Silvia Varricchio, Gennaro Ilardi, Massimo Mascolo, Stefania Staibano, Antonio Lavecchia, Pia Ragno, Carmine Selleri, Gianni Marone, Marco Matucci-Cerinic, Amato de Paulis, Nunzia Montuori
Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by fibrosis, alteration in the microvasculature and immunologic abnormalities. It has been hypothesized that an abnormal redox state could regulate the persistent fibrotic phenotype in SSc patients. N -Formyl peptide receptors (FPRs) are chemotactic receptors overexpressed in fibroblasts derived from SSc patients. In this study, we demonstrated that stimulation of FPRs promotes the generation of reactive oxygen species (ROS) in skin fibroblasts...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29528792/selumetinib-in-combination-with-dacarbazine-in-patients-with-metastatic-uveal-melanoma-a-phase-iii-multicenter-randomized-trial-sumit
#7
Richard D Carvajal, Sophie Piperno-Neumann, Ellen Kapiteijn, Paul B Chapman, Stephen Frank, Anthony M Joshua, Josep M Piulats, Pascal Wolter, Veronique Cocquyt, Bartosz Chmielowski, T R Jeffry Evans, Lauris Gastaud, Gerald Linette, Carola Berking, Jacob Schachter, Manuel J Rodrigues, Alexander N Shoushtari, Delyth Clemett, Dana Ghiorghiu, Gabriella Mariani, Shirley Spratt, Susan Lovick, Peter Barker, Elaine Kilgour, Zhongwu Lai, Gary K Schwartz, Paul Nathan
Purpose Uveal melanoma is the most common primary intraocular malignancy in adults with no effective systemic treatment option in the metastatic setting. Selumetinib (AZD6244, ARRY-142886) is an oral, potent, and selective MEK1/2 inhibitor with a short half-life, which demonstrated single-agent activity in patients with metastatic uveal melanoma in a randomized phase II trial. Methods The Selumetinib (AZD6244: ARRY-142886) (Hyd-Sulfate) in Metastatic Uveal Melanoma (SUMIT) study was a phase III, double-blind trial ( ClinicalTrial...
April 20, 2018: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/29526823/antitumor-efficacy-of-dual-blockade-of-egfr-signaling-by-osimertinib-in-combination-with-selumetinib-or-cetuximab-in-activated-egfr-human-nclc-tumor-models
#8
Carminia Maria Della Corte, Vincenza Ciaramella, Claudia Cardone, Silvia La Monica, Roberta Alfieri, Pier Giorgio Petronini, Umberto Malapelle, Elena Vigliar, Francesco Pepe, Giancarlo Troncone, Maria Domenica Castellone, Teresa Troiani, Erika Martinelli, Fortunato Ciardiello, Floriana Morgillo
INTRODUCTION: Osimertinib showed great clinical efficacy for activated-EGFR NCLC patient treatment. The aim of this work was to test the efficacy of a complete EGFR-inhibition by osimertinib plus the monoclonal antibody cetuximab or the MEK1/2-inhibitor selumetinib in EGFR-mutated NCLC in vivo models. METHODS: We evaluated combinations of osimertinib plus selumetinib/cetuximab in HCC827 (E746-A759del/T790M-), H1975 (L858R/T790M+), and PC9-T790M (E746-A759del /T790M+) xenografts in second-line therapy after the development of resistance to osimertinib, and in first-line therapy, and we explored mechanisms of resistance to these treatments...
June 2018: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/29423085/the-anti-rheumatic-drug-leflunomide-synergizes-with-mek-inhibition-to-suppress-melanoma-growth
#9
Kimberley Hanson, Stephen R Robinson, Karamallah Al-Yousuf, Adam E Hendry, Darren W Sexton, Victoria Sherwood, Grant N Wheeler
Cutaneous melanoma, which develops from the pigment producing cells called melanocytes, is the most deadly form of skin cancer. Unlike the majority of other cancers, the incidence rates of melanoma are still on the rise and the treatment options currently available are being hindered by resistance, limited response rates and adverse toxicity. We have previously shown that an FDA approved drug leflunomide, used for rheumatoid arthritis (RA), also holds potential therapeutic value in treating melanoma especially if used in combination with the mutant BRAF inhibitor, vemurafenib...
January 9, 2018: Oncotarget
https://www.readbyqxmd.com/read/29348467/efficacy-of-mek-inhibition-in-a-k-ras-driven-cholangiocarcinoma-preclinical-model
#10
Mingjie Dong, Xianqiong Liu, Katja Evert, Kirsten Utpatel, Michele Peters, Shanshan Zhang, Zhong Xu, Li Che, Antonio Cigliano, Silvia Ribback, Frank Dombrowski, Antonio Cossu, John Gordan, Diego F Calvisi, Matthias Evert, Yan Liu, Xin Chen
Intrahepatic cholangiocarcinoma (iCCA) is a deadly malignancy with limited treatment options. Gain-of-function mutations in K-Ras is a very frequent alteration, occurring in ~15 to 25% of human iCCA patients. Here, we established a new iCCA model by expressing activated forms of Notch1 (NICD) and K-Ras (K-RasV12D ) in the mouse liver (K-Ras/NICD mice). Furthermore, we investigated the therapeutic potential of MEK inhibitors in vitro and in vivo using human CCA cell lines and K-Ras/NICD mice, respectively. Treatment with U0126, PD901, and Selumetinib MEK inhibitors triggered growth restraint in all CCA cell lines tested, with the most pronounced growth suppressive effects being observed in K-Ras mutant cells...
January 18, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29296181/correlation-between-mek-signature-and-ras-gene-alteration-in-advanced-gastric-cancer
#11
Soomin Ahn, Roz Brant, Alan Sharpe, Jonathan R Dry, Darren R Hodgson, Elaine Kilgour, Kyung Kim, Seung Tae Kim, Se Hoon Park, Won Ki Kang, Kyoung-Mee Kim, Jeeyun Lee
MEK inhibitor (selumetinib) is a potent, orally active inhibitor of MAPK/ERK pathway. It is important to develop an accurate and robust method indicative of RAS pathway activity to stratify potential patients who can benefit from selumetinib treatment in gastric cancer (GC). First, we surveyed the sensitivity to selumetinib in a panel of 22 GC cell lines and correlated with MEK signature to selumetinib sensitivity. Next, we analyzed MEK signature via nanostring assay in two Asian cohorts using clinical samples ( n = 218) and then performed a correlative analysis with MEK signature status and KRAS genotype in GC...
December 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/29216787/mek-inhibitors-under-development-for-treatment-of-non-small-cell-lung-cancer
#12
REVIEW
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...
January 2018: 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
#13
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...
January 1, 2018: Japanese Journal of Clinical Oncology
https://www.readbyqxmd.com/read/29100278/somatic-mutations-in-salivary-duct-carcinoma-and-potential-therapeutic-targets
#14
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
#15
(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
#16
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...
January 2018: Experimental Neurology
https://www.readbyqxmd.com/read/29045535/select-2-a-phase-ii-double-blind-randomized-placebo-controlled-study-to-assess-the-efficacy-of-selumetinib-plus-docetaxel-as-a-second-line-treatment-of-patients-with-advanced-or-metastatic-non-small-cell-lung-cancer
#17
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 randomized (2 : 2 : 1) to selumetinib 75 mg b...
December 1, 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
#18
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...
May 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
#19
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)...
November 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
#20
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
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