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https://www.readbyqxmd.com/read/29324592/frequent-subclinical-macular-changes-in-combined-braf-mek-inhibition-with-high-dose-hydroxychloroquine-as-treatment-for-advanced-metastatic-braf-mutant-melanoma-preliminary-results-from-a-phase-i-ii-clinical-treatment-trial
#1
Akosua A Nti, Leona W Serrano, Harpal S Sandhu, Katherine E Uyhazi, Ilaina D Edelstein, Elaine J Zhou, Scott Bowman, Delu Song, Tara C Gangadhar, Lynn M Schuchter, Sheryl Mitnick, Alexander Huang, Charles W Nichols, Ravi K Amaravadi, Benjamin J Kim, Tomas S Aleman
PURPOSE: To assess the potential ocular toxicity of a combined BRAF inhibition (BRAFi) + MEK inhibition (MEKi) + hydroxychloroquine (HCQ) regime used to treat metastatic BRAF mutant melanoma. METHODS: Patients with stage IV metastatic melanoma and BRAF V600E mutations (n = 11, 31-68 years of age) were included. Treatment was with oral dabrafenib, 150 mg bid, trametinib, 2 mg/day, and HCQ, 400 mg to 600 mg bid. An ophthalmic examination, spectral domain optical coherence tomography, near-infrared and short-wavelength fundus autofluorescence, and static perimetry were performed at baseline, 1 month, and q/6 months after treatment...
January 10, 2018: Retina
https://www.readbyqxmd.com/read/29315294/the-oral-vegf-receptor-tyrosine-kinase-inhibitor-pazopanib-in-combination-with-the-mek-inhibitor-trametinib-in-advanced-cholangiocarcinoma
#2
Rachna T Shroff, Mark Yarchoan, Ashley O'Connor, Denise Gallagher, Marianna L Zahurak, Gary Rosner, Chimela Ohaji, Susan Sartorius-Mergenthaler, Rose Parkinson, Vivek Subbiah, Ralph Zinner, Nilofer S Azad
This corrects the article DOI: 10.1038/bjc.2017.119.
January 9, 2018: British Journal of Cancer
https://www.readbyqxmd.com/read/29312543/dual-targeting-of-her3-and-mek-may-overcome-her3-dependent-drug-resistance-of-colon-cancers
#3
Giulia Bon, Rossella Loria, Carla Azzurra Amoreo, Alessandra Verdina, Isabella Sperduti, Arianna Mastrofrancesco, Silvia Soddu, Maria Grazia Diodoro, Marcella Mottolese, Matilde Todaro, Giorgio Stassi, Michele Milella, Ruggero De Maria, Rita Falcioni
Although the medical treatment of colorectal cancer has evolved greatly in the last years, a significant portion of early-stage patients develops recurrence after therapies. The current clinical trials are directed to evaluate new drug combinations and treatment schedules. By the use of patient-derived or established colon cancer cell lines, we found that the tyrosine kinase receptor HER3 is involved in the mechanisms of resistance to therapies. In agreement, the immunohistochemical analysis of total and phospho-HER3 expression in 185 colorectal cancer specimens revealed a significant correlation with lower disease-free survival...
December 12, 2017: Oncotarget
https://www.readbyqxmd.com/read/29295876/rapid-clinical-and-radiographic-response-with-combined-dabrafenib-and-trametinib-in-adults-with-braf-mutated-high-grade-glioma
#4
Tanner M Johanns, Cole J Ferguson, Patrick M Grierson, Sonika Dahiya, George Ansstas
BRAF V600E mutations have been successfully treated with targeted therapy in melanoma, non-small cell lung cancer, and thyroid cancer. Interestingly, these mutations have also been identified in a subset of pediatric and adult brain tumors, with several cases reportedly responding to targeted therapy. However, these reports have been limited to single-agent BRAF inhibitor therapy and recurrent disease. Herein, we report dramatic clinical and radiographic responses to combination dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) in 2 adults with high-grade gliomas (HGGs), with 1 patient treated in the first-line setting...
January 2018: Journal of the National Comprehensive Cancer Network: JNCCN
https://www.readbyqxmd.com/read/29282298/%C3%AE-catenin-mrna-silencing-and-mek-inhibition-display-synergistic-efficacy-in-preclinical-tumor-models
#5
Shanthi Ganesh, Xue Shui, Kevin Craig, Martin Koser, Girish R Chopda, Wendy A Cyr, Chengjung Lai, Henryk Dudek, Weimin Wang, Bob Brown, Marc Abrams
Colorectal carcinomas (CRC) harbor well-defined genetic abnormalities including aberrant activation of Wnt/β-catenin and MAPK pathways, often simultaneously. While the MAPK pathway can be targeted using potent small molecule drugs, including BRAF and MEK inhibitors, β-catenin inhibition has been historically challenging. RNA interference (RNAi) approaches have advanced to the stage of clinical viability, and are especially well-suited for transcriptional modulators such as β-catenin. In this study, we report therapeutic effects of combined targeting of these pathways with pharmacological agents...
December 27, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29259009/loss-of-rassf4-expression-in-multiple-myeloma-promotes-ras-driven-malignant-progression
#6
Eva De Smedt, Ken Maes, Stefaan Verhulst, Hui Liu, Alboukadel Kassambara, Anke Maes, Nicolas Robert, Carlo Heirman, Andrew Cakana, Dirk Hose, Karine Breckpot, Leo A van Grunsven, Kim De Veirman, Eline Menu, Karin Vanderkerken, Jerome Moreaux, Elke De Bruyne
RAS mutations occur frequently in multiple myeloma (MM), but apart from driving progression they can also stimulate antitumor effects by activating tumor suppressive RASSF proteins. While this family of death effector molecules are often silenced in cancers, functional data about RASSF proteins in MM are lacking. Here we report that RASSF4 is downregulated during MM progression and correlates with a poor prognosis. Promoter methylation analysis in human cell lines revealed an inverse correlation between RASSF4 mRNA levels and methylation status...
December 19, 2017: Cancer Research
https://www.readbyqxmd.com/read/29239458/treatment-of-advanced-melanoma-a-changing-landscape
#7
Adriana Hepner, Alessandra Salgues, Carlos A Dos Anjos, Marina Sahade, Veridiana P Camargo, Bernardo Garicochea, Alexander N Shoushtari, Michael A Postow, Gustavo S Fernandes, Rodrigo R Munhoz
Following decades of relative ostracism, advances in the treatment of melanoma have brought a new reality for patients, physicians and researchers. While antibodies targeting molecules involved in the modulation of the interaction between melanoma and immune cells changed the meaning of the term "cancer immunotherapy," a better characterization of the molecular aberrations involved in melanoma carcinogenesis prompted the development of inhibitors of the mitogen-activated protein kinase pathway (MAPK) that also led to significant improvements both in response rates and survival...
September 2017: Revista da Associação Médica Brasileira
https://www.readbyqxmd.com/read/29237804/inhibiting-nuclear-phospho-progesterone-receptor-enhances-antitumor-activity-of-onapristone-in-uterine-cancer
#8
Yan Huang, Wei Hu, Jie Huang, Fanrong Shen, Yunjie Sun, Cristina Ivan, Sunila Pradeep, Robert Dood, Monika Haemmerle, Dahai Jiang, Lingegowda S Mangala, Kyunghee Noh, Jean M Hansen, Heather J Dalton, Rebecca Previs, Archana S Nagaraja, Michael McGuire, Nicholas B Jennings, Russell R Broaddus, Robert L Coleman, Anil K Sood
While progesterone receptor (PR)-targeted therapies are modestly active in patients with uterine cancer, their underlying molecular mechanisms are not well understood. The clinical use of such therapies is limited because of the lack of biomarkers that predict response to PR-agonists (progestins) or PR-antagonists (onapristone). Thus, understanding the underlying molecular mechanisms of action will provide an advance in developing novel combination therapies for cancer patients. Nuclear translocation of PR has been reported to be ligand-dependent or -independent...
December 13, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29222604/model-based-analysis-of-the-heterogeneity-in-the-tumour-size-dynamics-differentiates-vemurafenib-dabrafenib-and-trametinib-in-metastatic-melanoma
#9
Hitesh B Mistry, David Orrell, Raluca Eftimie
PURPOSE: Explore the heterogeneity in dynamics of tumour response to vemurafenib, dabrafenib and trametinib using routinely collected clinical trial imaging data. METHODS: Time-series imaging data from the phase III studies of vemurafenib, dabrafenib and trametinib were collected through a data repository. A mathematical model based on basic mechanisms of tumour growth was placed within a statistical modelling framework to analyse the data. RESULTS: The analysis revealed: (1) existence of homogeneity in drug response and resistance development within a patient; (2) tumour shrinkage rate does not relate to rate of resistance development; (3) vemurafenib and dabrafenib, two BRAF inhibitors, have different variability in tumour shrinkage rates...
December 8, 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/29216787/mek-inhibitors-under-development-for-treatment-of-non-small-cell-lung-cancer
#10
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/29215399/hemorrhage-of-liver-and-bone-metastases-as-a-result-of-rapid-response-to-dual-braf-mek-inhibition-in-metastatic-melanoma-a-case-report
#11
Tine Loyson, Emilie Werbrouck, Kevin Punie, Lawrence Bonne, Vincent Vandecaveye, Oliver Bechter
Combination therapy using a BRAF and MEK inhibitor significantly improves both progression-free and overall survival in patients with BRAF V600-mutated stage IV melanoma. Dual MAPK inhibition achieves an objective response in the majority of patients. We present a case of a woman with BRAF V600E-mutated malignant melanoma and rapidly progressing liver, bone, and lymph node metastases. The patient commenced dabrafenib and trametinib with clinical and biochemical signs of response after 2 days. On day 3 she developed grade 3 liver hemorrhage, which was successfully embolized...
December 5, 2017: Melanoma Research
https://www.readbyqxmd.com/read/29200156/sustained-response-to-targeted-therapy-in-a-patient-with-disseminated-anaplastic-pleomorphic-xanthoastrocytoma
#12
Nisreen Amayiri, Maisa Swaidan, Maysa Al-Hussaini, Hadeel Halalsheh, Anwar Al-Nassan, Awni Musharbash, Uri Tabori, Cynthia Hawkins, Eric Bouffet
Pleomorphic xanthoastrocytoma is a rare brain tumor with unique high frequency of BRAF V600E mutation which is plausible for targeted therapy. The anaplastic variant has generally worse prognosis. We present an adolescent patient with a disseminated relapse of anaplastic pleomorphic xanthoastrocytoma following surgery, radiotherapy, and chemotherapy. She had a dramatic and prolonged response to a BRAF inhibitor (Dabrafinib) and later to addition of a MEK inhibitor (Trametinib) on tumor progression. With minimal side effects and a good quality of life, the patient is alive more than 2 years after initiation of targeted therapy...
December 1, 2017: Journal of Pediatric Hematology/oncology
https://www.readbyqxmd.com/read/29197575/trametinib-suppresses-hiv-1-replication-by-interfering-with-the-disassembly-of-human-immunodeficiency-virus-type-1-capsid-core
#13
Takeo Dochi, Ayano Akita, Naoki Kishimoto, Nobutoki Takamune, Shogo Misumi
Our previous study showed that the phosphorylation of a highly conserved serine residue, Ser16 in the human immunodeficiency virus type 1 (HIV-1) capsid (CA) protein is promoted by virion-incorporated extracellular signal-regulated kinase 2 (ERK2) and required for proper peptidyl-prolyl isomerase (Pin1)-mediated uncoating. Interestingly, western blot analysis demonstrated that phosphorylated/activated mitogen-activated protein kinase kinase 1/2 (MEK1/2), the upstream activator of ERK2, as well as ERK2 are incorporated into virions...
November 29, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29196297/acetylsalicylic-acid-governs-the-effect-of-sorafenib-in-ras-mutant-cancers
#14
Heinz Hammerlindl, Dinoop Ravindran Menon, Sabrina Hammerlindl, Abdullah Al Emran, Joachim Torrano, Katrin Sproesser, Divya Thakkar, Min Xiao, Victoria G Atkinson, Brian Gabrielli, Nikolas K Haass, Meenhard Herlyn, Clemens Krepler, Helmut Schaider
PURPOSE: Identify and characterize novel combinations of sorafenib with anti-inflammatory painkillers to target difficult to treat RAS-mutant cancer. EXPERIMENTAL DESIGN: The cytotoxicity of acetylsalicylic acid (aspirin) in combination with the multikinase inhibitor sorafenib (Nexavar) was assessed in RAS-mutant cell lines in vitro. The underlying mechanism for the increased cytotoxicity was investigated using selective inhibitors and shRNA-mediated gene knockdown...
December 1, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29193645/mapk-inhibitors-induce-serine-peptidase-inhibitor-kazal-type-1-spink1-secretion-in-braf-v600e-mutant-colorectal-adenocarcinoma
#15
Kati Räsänen, Kien X Dang, Harri Mustonen, Tho H Ho, Susanna Lintula, Hannu Koistinen, Ulf-Håkan Stenman, Caj Haglund, Jakob Stenman
The mitogen-activated protein kinase (MAPK) pathway plays a central role in colorectal cancers (CRC). In particular, BRAF V600E-mutant tumors, which represent around 10% of CRCs, are refractory to current therapies. Over-expression and secretion of serine peptidase inhibitor Kazal type 1 (SPINK1) is observed in around 50% of CRCs and its serum level can be used as a biomarker for poor prognosis. Utilizing a recently developed Extendable Blocking Probe assay, we analyzed the BRAF mutation status in a CRC patient cohort (N=571) using tissue-derived RNA as the starting material...
November 28, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/29184034/mek-inhibitor-trametinib-does-not-prevent-the-growth-of-anaplastic-lymphoma-kinase-alk-addicted-neuroblastomas
#16
Ganesh Umapathy, Jikui Guan, Dan E Gustafsson, Niloufar Javanmardi, Diana Cervantes-Madrid, Anna Djos, Tommy Martinsson, Ruth H Palmer, Bengt Hallberg
Activation of the RAS-RAF-MEK-ERK signaling pathway is implicated in driving the initiation and progression of multiple cancers. Several inhibitors targeting the RAS-MAPK pathway are clinically approved as single- or polyagent therapies for patients with specific types of cancer. One example is the MEK inhibitor trametinib, which is included as a rational polytherapy strategy for treating EML4-ALK-positive, EGFR-activated, or KRAS-mutant lung cancers and neuroblastomas that also contain activating mutations in the RAS-MAPK pathway...
November 28, 2017: Science Signaling
https://www.readbyqxmd.com/read/29180761/combined-inhibition-of-mek-and-nuclear-erk-translocation-has-synergistic-antitumor-activity-in-melanoma-cells
#17
Rand Arafeh, Karen Flores, Alona Keren-Paz, Galia Maik-Rachline, Naomi Gutkind, Steven Rosenberg, Rony Seger, Yardena Samuels
Genetic alterations in BRAF, NRAS and NF1 that activate the ERK cascade, account for over 80% of metastatic melanomas. However, ERK cascade inhibitors have been proven beneficial almost exclusively for BRAF mutant melanomas. One of the hallmarks of the ERK cascade is the nuclear translocation of ERK1/2, which is important mainly for the induction of proliferation. This translocation can be inhibited by the NTS-derived peptide (EPE) that blocks the ERK1/2-importin7 interaction, inhibits the nuclear translocation of ERK1/2, and arrests active ERK1/2 in the cytoplasm...
November 27, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29180473/new-mechanisms-of-resistance-to-mek-inhibitors-in-melanoma-revealed-by-intravital-imaging
#18
Hailey E Brighton, Steven P Angus, Tao Bo, Jose Roques, Alicia C Tagliatela, David Darr, Kubra Karagoz, Noah Sciaky, Michael Gatza, Norman E Sharpless, Gary L Johnson, James E Bear
Targeted therapeutics that are initially effective in cancer patients nearly invariably engender resistance at some stage, an inherent challenge in the use of any molecular targeted drug in cancer settings. In this study, we evaluated resistance mechanisms arising in metastatic melanoma to MAPK pathway kinase inhibitors, as a strategy to identify candidate strategies to limit risks of resistance. To investigate longitudinal responses, we developed an intravital serial imaging approach that can directly visualize drug response in an inducible RAF-driven, autochthonous murine model of melanoma incorporating a fluorescent reporter allele (tdTomatoLSL)...
November 27, 2017: Cancer Research
https://www.readbyqxmd.com/read/29171936/braf-internal-deletions-and-resistance-to-braf-mek-inhibitor-therapy
#19
Douglas B Johnson, Merrida A Childress, Zachary R Chalmers, Garrett M Frampton, Siraj M Ali, Samuel M Rubinstein, David Fabrizio, Jeffrey S Ross, Sohail Balasubramanian, Vincent A Miller, Philip J Stephens, Jeffrey A Sosman, Christine M Lovly
BRAF and MEK inhibitors have improved clinical outcomes in advanced, BRAFV600 - mutated melanomas. Acquired resistance occurs in most patients, with numerous and diverse drivers. We obtained pre-treatment and progression biopsies from a patient who progressed on dabrafenib and trametinib. In addition to a preserved BRAFV600E mutation, an internal deletion (rearrangement) of BRAF was observed in the progression sample. This deletion involved exons 2-8, which includes the Ras-binding domain, and is analogous to previously documented BRAF fusions and splice variants known to reactivate RAS-RAF-MEK-ERK signaling...
November 24, 2017: Pigment Cell & Melanoma Research
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
#20
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
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