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https://www.readbyqxmd.com/read/29165815/development-and-validation-of-a-liquid-chromatography-tandem-mass-spectrometry-analytical-method-for-the-therapeutic-drug-monitoring-of-eight-novel-anticancer-drugs
#1
M Herbrink, N de Vries, H Rosing, A D R Huitema, B Nuijen, J H M Schellens, J H Beijnen
To support therapeutic drug monitoring (TDM) of patients with cancer, a fast and accurate method for simultaneous quantification of the registered anticancer drugs afatinib, axitinib, ceritinib, crizotinib, dabrafenib, enzalutamide, regorafenib and trametinib in human plasma using liquid chromatography tandem mass spectrometry was developed and validated. Human plasma samples were collected from treated patients and stored at -20 (o) C. Analytes and internal standards (stable isotopically labeled analytes) were extracted with acetonitrile...
November 22, 2017: Biomedical Chromatography: BMC
https://www.readbyqxmd.com/read/29161986/real-world-experience-with-targeted-therapy-for-the-treatment-of-anaplastic-thyroid-carcinoma
#2
Priyanka Iyer, Ramona Dadu, Renata Ferrarotto, Naifa Busaidy, Mouhammed Amir Habra, Mark Zafereo, Neil D Gross, Kenneth Hess, Maria Gule-Monroe, Michelle D Williams, Maria Cabanillas
BACKGROUND: Patients with anaplastic thyroid cancer (ATC) have a dismal prognosis despite systemic cytotoxic chemotherapy. Our objective was to study the efficacy and safety of targeted therapy in ATC patients when used outside of a clinical trial. METHODS: This is a retrospective review from April 2015 to May 2016 at a single academic institution where we studied 16 ATC patients receiving targeted therapy outside of a clinical trial. Ten patients (8 BRAF wild-type and 2 BRAF V600E mutant) were started on lenvatinib and 6 with BRAF V600E mutated tumors received the combination of dabrafenib plus trametinib...
November 22, 2017: Thyroid: Official Journal of the American Thyroid Association
https://www.readbyqxmd.com/read/29161237/bilateral-visual-field-defects-in-a-patient-treated-with-the-mek-and-braf-inhibitors-trametinib-and-dabrafenib-for-melanoma-of-unknown-origin
#3
Jakob Siedlecki, Marc Mackert, Armin Wolf, Carola Berking, Siegfried G Priglinger, Kirsten Eibl-Lindner
INTRODUCTION: Although the introduction of BRAF and MEK inhibitors has greatly enhanced treatment possibilities in advanced BRAFV600-mutated melanoma, class-related toxicities are rather frequent and often involve the eye. Ophthalmologic side effects most commonly include central/diffuse serous retinopathy and retinal vein occlusion. Affection of the optic nerve head however has not been described clinically. CASE REPORT: A 29-year-old man presented in our eye clinic with bilateral blurred vision...
April 17, 2017: Retinal Cases & Brief Reports
https://www.readbyqxmd.com/read/29156677/overcoming-resistance-to-single-agent-therapy-for-oncogenic-braf-gene-fusions-via-combinatorial-targeting-of-mapk-and-pi3k-mtor-signaling-pathways
#4
Payal Jain, Amanda Silva, Harry J Han, Shih-Shan Lang, Yuankun Zhu, Katie Boucher, Tiffany E Smith, Aesha Vakil, Patrick Diviney, Namrata Choudhari, Pichai Raman, Christine M Busch, Tim Delaney, Xiaodong Yang, Aleksandra K Olow, Sabine Mueller, Daphne Haas-Kogan, Elizabeth Fox, Phillip B Storm, Adam C Resnick, Angela J Waanders
Pediatric low-grade gliomas (PLGGs) are frequently associated with activating BRAF gene fusions, such as KIAA1549-BRAF, that aberrantly drive the mitogen activated protein kinase (MAPK) pathway. Although RAF inhibitors (RAFi) have been proven effective in BRAF-V600E mutant tumors, we have previously shown how the KIAA1549-BRAF fusion can be paradoxically activated by RAFi. While newer classes of RAFi, such as PLX8394, have now been shown to inhibit MAPK activation by KIAA1549-BRAF, we sought to identify alternative MAPK pathway targeting strategies using clinically relevant MEK inhibitors (MEKi), along with potential escape mechanisms of acquired resistance to single-agent MAPK pathway therapies...
October 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29149136/mapk-pathway-targeted-therapies-care-and-management-of-unique-toxicities-in-patients-with-advanced-melanoma%C3%A2
#5
Krista M Rubin
BACKGROUND: Agents targeting the MAPK pathway, including inhibitors of BRAF and MEK, have dramatically transformed the treatment landscape for patients with BRAF-mutant metastatic melanoma. Although generally well tolerated, targeted agents were associated with unique toxicities.
. OBJECTIVES: This article aims to provide nurses with an overview of the key toxicities and associated management strategies of the characteristic adverse event (AE) profile associated with agents targeting the MAPK pathway...
December 1, 2017: Clinical Journal of Oncology Nursing
https://www.readbyqxmd.com/read/29142786/extraordinary-clinical-benefit-to-sequential-treatment-with-targeted-therapy-and-immunotherapy-of-a-braf-v600e-and-pd-l1-positive-metastatic-lung-adenocarcinoma
#6
Shuyu D Li, Annia Martial, Alexa B Schrock, Jane J Liu
Background: The treatment algorithm for metastatic non-small cell lung cancers (NSCLCs) has been evolving rapidly due to the development of new therapeutic agents. Although guidelines are provided by National Comprehensive Cancer Network (NCCN) for treatment options according to biomarker testing results, sequentially applying the three main modalities (chemotherapy, targeted therapy and immunotherapy) remains an ad hoc practice in clinic. In light of recent FDA approval of dabrafenib and trametinib combination for metastatic NSCLCs with BRAF V600E mutation, one question arises due to insufficient clinical data is if the targeted therapy should be used before immunotherapy in patients with both BRAF V600E and PD-L1 expression...
2017: Experimental Hematology & Oncology
https://www.readbyqxmd.com/read/29133622/ceritinib-enhances-the-efficacy-of-trametinib-in-braf-nras-wild-type-melanoma-cell-lines
#7
Daniel Verduzco, Brent M Kuenzi, Fumi Kinose, Vernon K Sondak, Zeynep Eroglu, Uwe Rix, Keiran S M Smalley
Targeted therapy options are currently lacking for the heterogeneous population of patients whose melanomas lack BRAF or NRAS mutations (~35% of cases). We undertook a chemical biology screen to identify potential novel drug targets for this understudied group of tumors. Screening a panel of 8 BRAF/NRAS-WT melanoma cell lines against 240 targeted drugs identified ceritinib and trametinib as potential hits with single agent activity. Ceritinib enhanced the efficacy of trametinib across the majority of the BRAF/NRAS-WT cell lines, and the combination showed increased cytotoxicity in both 3D spheroid culture and long-term colony formation experiments...
November 13, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29133594/competitive-kinase-enrichment-proteomics-reveals-that-abemaciclib-inhibits-gsk3%C3%AE-and-activates-wnt-signaling
#8
Emily M Cousins, Dennis Goldfarb, Feng Yan, Jose Roques, David B Darr, Gary L Johnson, Michael B Major
The cellular and organismal phenotypic response to a small-molecule kinase inhibitor is defined collectively by the inhibitor's targets and their functions. The selectivity of small-molecule kinase inhibitors is commonly determined in vitro, using purified kinases and substrates. Recently, competitive chemical proteomics has emerged as a complementary, unbiased, cell-based methodology to define the target landscape of kinase inhibitors. Here, we evaluated and optimized a competitive multiplexed inhibitor bead mass spectrometry (MIB/MS) platform using cell lysates, live cells, and treated mice...
November 13, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29127119/rasa1-and-nf1-are-preferentially-co-mutated-and-define-a-distinct-genetic-subset-of-smokingassociated-non-small-cell-lung-carcinomas-sensitive-to-mek-inhibition
#9
Takuo Hayashi, Patrice Desmeules, Roger S Smith, Alexander Drilon, Romel Somwar, Marc Ladanyi
PURPOSE: Ras-GTPase activating proteins (RasGAPs), notably NF1 and RASA1, mediate negative control of the RAS/MAPK pathway. We evaluated clinical and molecular characteristics of NSCLC with RASA1 mutations in comparison with NF1-mutated cases. EXPERIMENTAL DESIGN: Large genomic datasets of NSCLC [MSK-IMPACT™ dataset at MSKCC (n=2004), TCGA combined lung cancer dataset (n=1144)] were analyzed to define concurrent mutations and clinical features of RASA1-mutated NSCLCs...
November 10, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29127087/dabrafenib-plus-trametinib-is-active-in-braf-v600e-anaplastic-thyroid-cancer
#10
(no author information available yet)
Dual BRAF/MEK inhibition achieves responses in 69% of BRAFV(600E) anaplastic thyroid cancers (ATC).
November 10, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/29121415/efficacy-and-safety-of-trametinib-in-japanese-patients-with-advanced-biliary-tract-cancers-refractory-to-gemcitabine
#11
Masafumi Ikeda, Tatsuya Ioka, Akira Fukutomi, Chigusa Morizane, Akiyoshi Kasuga, Hideaki Takahashi, Akiko Todaka, Takuji Okusaka, Caretha L Creasy, Shelby Gorman, Daniel J Felitsky, Mikiro Kobayashi, Fanghong Zhang, Junji Furuse
Gemcitabine-based therapy remains the mainstay of treatment for patients with biliary tract cancers (BTCs) with no second-line treatment(s) established yet. Aberrant activation of MAPK pathway in patients with BTC indicates its importance in BTC. Trametinib is a potent, highly selective, allosteric non-competitive inhibitor of MEK1/MEK2. In this Phase IIa open-label, single-arm study, we investigated efficacy and safety of trametinib in Japanese patients with advanced BTC refractory to gemcitabine-based therapy...
November 9, 2017: Cancer Science
https://www.readbyqxmd.com/read/29097496/response-to-mek-inhibition-with-trametinib-and-tyrosine-kinase-inhibition-with-imatinib-in-multifocal-histiocytic-sarcoma
#12
Sophie Voruz, Anne Cairoli, Olaia Naveiras, Laurence de Leval, Edoardo Missiaglia, Krisztian Homicsko, Olivier Michielin, Sabine Blum
No abstract text is available yet for this article.
November 2, 2017: Haematologica
https://www.readbyqxmd.com/read/29079711/histone-deacetylase-inhibition-enhances-the-antitumor-activity-of-a-mek-inhibitor-in-lung-cancer-cells-harboring-ras-mutations
#13
Tadaaki Yamada, Joseph M Amann, Azusa Tanimoto, Hirokazu Taniguchi, Takehito Shukuya, Cynthia Timmers, Seiji Yano, Konstantin Shilo, David P Carbone
Non-small-cell lung cancer (NSCLC) can be identified by precise molecular subsets based on genomic alterations that drive tumorigenesis and include mutations in EGFR, KRAS, and various ALK fusions. However, despite effective treatments for EGFR and ALK, promising therapeutics have not been developed for patients with KRAS mutations. It has been reported that one way the RAS-ERK pathway contributes to tumorigenesis is by affecting stability and localization of FOXO3a protein, an important regulator of cell death and the cell cycle...
October 27, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29072975/dabrafenib-and-trametinib-treatment-in-patients-with-locally-advanced-or-metastatic-braf-v600-mutant-anaplastic-thyroid-cancer
#14
Vivek Subbiah, Robert J Kreitman, Zev A Wainberg, Jae Yong Cho, Jan H M Schellens, Jean Charles Soria, Patrick Y Wen, Christoph Zielinski, Maria E Cabanillas, Gladys Urbanowitz, Bijoyesh Mookerjee, Dazhe Wang, Fatima Rangwala, Bhumsuk Keam
Purpose We report the efficacy and safety of dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) combination therapy in BRAF V600E-mutated anaplastic thyroid cancer, a rare, aggressive, and highly lethal malignancy with poor patient outcomes and no systemic therapies with clinical benefit. Methods In this phase II, open-label trial, patients with predefined BRAF V600E-mutated malignancies received dabrafenib 150 mg twice daily and trametinib 2 mg once daily until unacceptable toxicity, disease progression, or death...
October 26, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/29064427/the-mek-inhibitors-trametinib-and-cobimetinib-induce-a-type-i-interferon-response-in-human-keratinocytes
#15
Daniela Lulli, Maria Luigia Carbone, Saveria Pastore
Mitogen-activated protein kinase kinases (MEK) 1 and 2 have crucial roles in tumorigenesis, cell proliferation, and protection from apoptosis, and their inhibition is therefore an attractive therapeutic strategy in cancer. Orally available and highly selective MEK inhibitors have been developed and assessed in numerous clinical trials, either alone or in combination with cytotoxic chemotherapy and/or other targeted agents. Of note, a complex picture of class-specific adverse effects associates with these drugs, frequently including inflammatory skin rash...
October 24, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29050517/the-safety-and-efficacy-of-dabrafenib-and-trametinib-for-the-treatment-of-melanoma
#16
Sarah Knispel, Lisa Zimmer, Theodora Kanaki, Selma Ugurel, Dirk Schadendorf, Elisabeth Livingstone
The introduction of BRAF and MEK inhibitors into clinical practice improved the prognosis of metastatic melanoma patients. The combination of BRAF inhibitor dabrafenib with MEK inhibitor trametinib has shown its superiority to single agent therapy and is characterized by a tolerable spectrum of adverse events which shows a decrease in incidence over time on treatment. Areas covered: The current scientific literature on safety and adverse events (AEs) related to BRAF and MEK-inhibition has been investigated with special focus on the large phase 3 studies (COMBI-v, COMBI-d and CoBRIM) as well as recent updates presented at oncology and melanoma meetings...
October 20, 2017: Expert Opinion on Drug Safety
https://www.readbyqxmd.com/read/28991513/long-term-outcomes-in-patients-with-braf-v600-mutant-metastatic-melanoma-who-received-dabrafenib-combined-with-trametinib
#17
Georgina V Long, Zeynep Eroglu, Jeffrey Infante, Sapna Patel, Adil Daud, Douglas B Johnson, Rene Gonzalez, Richard Kefford, Omid Hamid, Lynn Schuchter, Jonathan Cebon, William Sharfman, Robert McWilliams, Mario Sznol, Suman Redhu, Eduard Gasal, Bijoyesh Mookerjee, Jeffrey Weber, Keith T Flaherty
Purpose To report 5-year landmark analysis efficacy and safety outcomes in patients with BRAF V600-mutant metastatic melanoma (MM) who received BRAF inhibitor dabrafenib (D) and MEK inhibitor trametinib (T) combination therapy versus D monotherapy in the randomized phase II BRF113220 study part C. Patients and Methods BRAF inhibitor-naive patients with BRAF V600-mutant MM were randomly assigned 1:1:1 to receive D 150 mg twice a day, D 150 mg twice a day plus T 1 mg once daily, or D 150 mg twice a day plus T 2 mg once daily (D + T 150/2)...
October 9, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28984141/dabrafenib-and-trametinib-in-brafv600e-mutated-glioma
#18
Nicholas F Brown, Thomas Carter, Neil Kitchen, Paul Mulholland
BRAFV600E mutations have been identified in a number of glioma subtypes, most frequently in pleomorphic xanthoastrocytoma, ganglioglioma, pilocytic astrocytoma, and epithelioid glioblastoma. Although the development of BRAF inhibitors has dramatically improved the clinical outcome for patients with BRAFV600E mutant tumors, resistance develops in a majority of patients due to reactivation of the MAPK pathway. Addition of MEK inhibition to BRAF inhibition improves survival. Here we report successful treatment of two patients with BRAFV600E mutant pleomorphic xanthoastrocytoma using the BRAF inhibitor dabrafenib in combination with the MEK inhibitor trametinib...
October 6, 2017: CNS Oncology
https://www.readbyqxmd.com/read/28982179/a-study-of-pd-l1-expression-in-kras-mutant-non-small-cell-lung-cancer-cell-lines-exposed-to-relevant-targeted-treatments
#19
Anna Minchom, Parames Thavasu, Zai Ahmad, Adam Stewart, Alexandros Georgiou, Mary E R O'Brien, Sanjay Popat, Jaishree Bhosle, Timothy A Yap, Johann de Bono, Udai Banerji
We investigated PD-L1 changes in response to MEK and AKT inhibitors in KRAS mutant lung adenocarcinoma (adeno-NSCLC). PD-L1 expression was quantified using immunofluorescence and co-culture with a jurkat cell-line transfected with NFAT-luciferase was used to study if changes in PD-L1 expression in cancer cell lines were functionally relevant. Five KRAS mutant cell lines with high PD-L1 expression (H441, H2291, H23, H2030 and A549) were exposed to GI50 inhibitor concentrations of a MEK inhibitor (trametinib) and an AKT inhibitor (AZD5363) for 3 weeks...
2017: PloS One
https://www.readbyqxmd.com/read/28972594/ras-pathway-mutations-as-predictive-biomarker-for-treatment-adaptation-in-pediatric-b-cell-precursor-acute-lymphoblastic-leukemia
#20
I S Jerchel, A Q Hoogkamer, I M Ariës, E M P Steeghs, J M Boer, N J M Besselink, A Boeree, C van de Ven, H A de Groot-Kruseman, V de Haas, M A Horstmann, G Escherich, C M Zwaan, E Cuppen, M J Koudijs, R Pieters, M L den Boer
RAS pathway mutations have been linked to relapse and chemotherapy resistance in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL). However, comprehensive data on the frequency and prognostic value of subclonal mutations in well-defined subgroups using highly sensitive and quantitative methods is lacking. Targeted deep sequencing of 13 RAS-pathway genes was performed in 461 pediatric BCP-ALL cases at initial diagnosis and in 19 diagnosis-relapse pairs. Mutations were present in 44.2% of patients, with 24...
October 3, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
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