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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/29215399/hemorrhage-of-liver-and-bone-metastases-as-a-result-of-rapid-response-to-dual-braf-mek-inhibition-in-metastatic-melanoma-a-case-report
#2
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/29214089/systemic-treatment-of-metastatic-conjunctival-melanoma
#3
Simão Pinto Torres, Teresa André, Emanuel Gouveia, Lívio Costa, Maria José Passos
Conjunctival melanoma (CM) is an exceptionally rare tumor, with a propensity for local and distant recurrence, with the lungs, skin, liver, and brain being the most common sites of metastasis. Recent progress in systemic treatments, with checkpoint inhibitors and targeted therapies blocking BRAF and MEK, has redefined the standard of care of advanced unresectable and metastatic melanoma. Although most trials did not include patients with conjunctival melanoma, its close molecular and genetic relationship to cutaneous melanoma might suggest a similar response to these novel agents...
2017: Case Reports in Oncological Medicine
https://www.readbyqxmd.com/read/29212029/melk-promotes-melanoma-growth-by-stimulating-the-nf-%C3%AE%C2%BAb-pathway
#4
Radoslav Janostiak, Navin Rauniyar, TuKiet T Lam, Jianhong Ou, Lihua J Zhu, Michael R Green, Narendra Wajapeyee
Melanoma accounts for more than 80% of skin cancer-related deaths, and current therapies provide only short-term benefit to patients. Here, we show in melanoma cells that maternal embryonic leucine zipper kinase (MELK) is transcriptionally upregulated by the MAPK pathway via transcription factor E2F1. MELK knockdown or pharmacological inhibition blocked melanoma growth and enhanced the effectiveness of BRAFV600E inhibitor against melanoma cells. To identify mediators of MELK function, we performed stable isotope labeling with amino acids in cell culture (SILAC) and identified 469 proteins that had downregulated phosphorylation after MELK inhibition...
December 5, 2017: Cell Reports
https://www.readbyqxmd.com/read/29212027/melanoma-therapeutic-strategies-that-select-against-resistance-by-exploiting-myc-driven-evolutionary-convergence
#5
Katherine R Singleton, Lorin Crawford, Elizabeth Tsui, Haley E Manchester, Ophelia Maertens, Xiaojing Liu, Maria V Liberti, Anniefer N Magpusao, Elizabeth M Stein, Jennifer P Tingley, Dennie T Frederick, Genevieve M Boland, Keith T Flaherty, Shannon J McCall, Clemens Krepler, Katrin Sproesser, Meenhard Herlyn, Drew J Adams, Jason W Locasale, Karen Cichowski, Sayan Mukherjee, Kris C Wood
Diverse pathways drive resistance to BRAF/MEK inhibitors in BRAF-mutant melanoma, suggesting that durable control of resistance will be a challenge. By combining statistical modeling of genomic data from matched pre-treatment and post-relapse patient tumors with functional interrogation of >20 in vitro and in vivo resistance models, we discovered that major pathways of resistance converge to activate the transcription factor, c-MYC (MYC). MYC expression and pathway gene signatures were suppressed following drug treatment, and then rebounded during progression...
December 5, 2017: Cell Reports
https://www.readbyqxmd.com/read/29210065/hdac-inhibitors-restore-braf-inhibitor-sensitivity-by-altering-pi3k-and-survival-signalling-in-a-subset-of-melanoma
#6
Stuart J Gallagher, Dilini Gunatilake, Kimberley A Beaumont, Danae M Sharp, Jessamy C Tiffen, Anja Heinemann, Wolfgang Weninger, Nikolas K Haass, James S Wilmott, Jason Madore, Peter M Ferguson, Helen Rizos, Peter Hersey
Mutations in BRAF activate oncogenic MAPK signalling in almost half of cutaneous melanomas. Inhibitors of BRAF (BRAFi) and its target MEK are widely used to treat melanoma patients with BRAF mutations but unfortunately acquired resistance occurs in the majority of patients. Resistance results from mutations or non-genomic changes that either reactivate MAPK signalling or activate other pathways that provide alternate survival and growth signalling. Here we show the histone deacetylase inhibitor (HDACi) panobinostat overcomes BRAFi resistance in melanoma, but this is dependent on the resistant cells showing a partial response to BRAFi treatment...
December 6, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/29204524/distant-intracranial-failure-in-melanoma-brain-metastases-treated-with-stereotactic-radiosurgery-in-the-era-of-immunotherapy-and-targeted-agents
#7
Sahaja Acharya, Mustafaa Mahmood, Daniel Mullen, Deshan Yang, Christina I Tsien, Jiayi Huang, Stephanie M Perkins, Keith Rich, Michael Chicoine, Eric Leuthardt, Joshua Dowling, Gavin Dunn, Jesse Keller, Clifford G Robinson, Christopher Abraham
Purpose: Stereotactic radiosurgery (SRS) in combination with immunotherapy (IMT) or targeted therapy is increasingly being used in the setting of melanoma brain metastases (MBMs). The synergistic properties of combination therapy are not well understood. We compared the distant intracranial failure rates of intact MBMs treated with SRS, SRS + IMT, and SRS + targeted therapy. Methods and materials: Combination therapy was defined as delivery of SRS within 3 months of IMT (anti-CTLA-4 /anti-PD-1 therapy) or targeted therapy (BRAF/MEK inhibitors)...
October 2017: Advances in Radiation Oncology
https://www.readbyqxmd.com/read/29200156/sustained-response-to-targeted-therapy-in-a-patient-with-disseminated-anaplastic-pleomorphic-xanthoastrocytoma
#8
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/29196297/acetylsalicylic-acid-governs-the-effect-of-sorafenib-in-ras-mutant-cancers
#9
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/29195116/pd-l1-status-does-not-predict-the-outcome-of-braf-inhibitor-therapy-in-metastatic-melanoma
#10
Katrin Schaper-Gerhardt, Steven Okoye, Rudolf Herbst, Jens Ulrich, Patrick Terheyden, Claudia Pföhler, Jochen S Utikal, Alexander Kreuter, Peter Mohr, Edgar Dippel, Imke Satzger, Antje Sucker, Dirk Schadendorf, Selma Ugurel, Ralf Gutzmer
BACKGROUND: Targeted therapies with BRAF plus MEK inhibitors (BRAFi; MEKi) represent the major treatment strategy for patients with BRAF-mutated metastatic melanoma (MM). Previous analyses suggested a correlation between programmed death-ligand 1 (PD-L1) expression in tumour tissues and the outcome of targeted therapies. This study investigated PD-L1 as a potential predictive biomarker of BRAFi-based targeted therapies in MM patients. PATIENTS AND METHODS: We analysed two independent cohorts of BRAF V600-mutated MM patients undergoing BRAFi-based therapies for PD-L1 expression in pre-treatment tumour tissues...
November 28, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/29193645/mapk-inhibitors-induce-serine-peptidase-inhibitor-kazal-type-1-spink1-secretion-in-braf-v600e-mutant-colorectal-adenocarcinoma
#11
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/29187493/braf-nras-and-c-kit-advanced-melanoma-clinico-pathological-features-targeted-therapy-strategies-and-survival
#12
Giovanni Ponti, Marco Manfredini, Stefano Greco, Giovanni Pellacani, Roberta Depenni, Aldo Tomasi, Monia Maccaferri, Stefano Cascinu
BACKGROUND/AIM: The mutational status of stage III and IV melanomas should be recognized in order to allow for targeted therapies. The aim of our study was the characterization of BRAF, NRAS and C-KIT melanoma patients, in order to define their optimal management. PATIENTS AND METHODS: Between 1991 and 2015, 63 mutated melanoma patients were treated and monitored during their diagnostic and therapeutic management at a single institution. RESULTS: BRAF-mutated melanoma patients were the most common, representing 70% of the study population, while NRAS- and C-KIT-mutated melanoma represented 19% and 11% respectively...
December 2017: Anticancer Research
https://www.readbyqxmd.com/read/29181212/uncommon-braf-mutations-associated-with-durable-response-to-immunotherapy-in-patients-with-metastatic-melanoma
#13
Brenen P Swofford, Jade Homsi
Melanoma is a disease process which has been increasing in incidence over the past three decades and metastatic melanoma carries a poor prognosis. Through genetic studies of this disease, it has been determined that the BRAF V600 mutation plays a major role in the pathophysiology of the disease and this has led to the utilization of targeted therapy (BRAF and MEK inhibitors) in its treatment. Other BRAF mutations (non-V600 mutations) are rare in melanoma and targeted therapy is not indicated for patients with these mutations due to reduced response rates...
2017: Case Reports in Oncological Medicine
https://www.readbyqxmd.com/read/29180872/therapeutic-efficacy-and-safety-of-combined-braf-and-mek-inhibition-in-patients-with-malignant-melanoma-a-meta-analysis
#14
Peng Chen, Fuchao Chen, Benhong Zhou
Background: Recent clinical studies have shown that initial therapy with combined BRAF and mitogen-activated extracellular signal-regulated kinase (MEK) inhibition is more effective in metastatic melanoma than single-agent BRAF inhibitors. However, the response rates with single-agent BRAF are low. Thus, the objective of this study was to conduct a meta-analysis of randomized controlled trials to compare the efficacy and adverse events risk between mono-therapy and combination therapy...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/29180761/combined-inhibition-of-mek-and-nuclear-erk-translocation-has-synergistic-antitumor-activity-in-melanoma-cells
#15
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
#16
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
#17
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/29167314/wnt-%C3%AE-catenin-pathway-activation-mediates-adaptive-resistance-to-braf-inhibition-in-colorectal-cancer
#18
Guangming Chen, Chenxi Gao, Xuan Gao, Dennis Han Zhang, Shih-Fan Kuan, Timothy F Burns, Jing Hu
One of the most encouraging developments in oncology has been the success of BRAF inhibitors in BRAF-mutant melanoma. However, in contrast to its striking efficacy in BRAF-mutant melanomas, BRAF inhibitor monotherapy is ineffective in BRAF-mutant colorectal cancer (CRC). While many studies on BRAF inhibitor resistance in CRC have focused on mechanisms underlying the reactivation of the EGFR/RAS/RAF/MEK/ERK pathway, the current study focuses on identifying novel adaptive signaling mechanisms, a fresh angle on CRC resistance to BRAF inhibition...
November 22, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29164492/advanced-melanoma-current-treatment-options-biomarkers-and-future-perspectives
#19
REVIEW
Elisa A Rozeman, Tim J A Dekker, John B A G Haanen, Christian U Blank
Malignant melanoma accounts for the highest number of deaths from skin cancer, and the prognosis of patients with stage IV disease has historically been poor. Novel insights into both mutations driving tumorigenesis and immune escape mechanisms of these tumors have led to effective treatment options that have revolutionized the treatment of this disease. Targeting the MAPK kinase pathway (with BRAF and MEK inhibitors), as well as targeting checkpoints, such as cytotoxic T-lymphocyte associated protein 4 (CTLA-4) or programmed death 1 (PD-1), have improved overall survival in patients with late-stage melanoma, and biomarker research for personalized therapy is ongoing for each of these treatment modalities...
November 21, 2017: American Journal of Clinical Dermatology
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
#20
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
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