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Vemurafenib

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https://www.readbyqxmd.com/read/29149136/mapk-pathway-targeted-therapies-care-and-management-of-unique-toxicities-in-patients-with-advanced-melanoma%C3%A2
#1
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/29137417/inhibition-of-retinoic-acid-receptor-%C3%AE-signaling-confers-glycolytic-dependence-and-sensitization-to-dichloroacetate-in-melanoma-cells
#2
Cecilie Abildgaard, Christina Dahl, Ahmad Abdul-Al, Annette Christensen, Per Guldberg
Dysregulation of metabolism during melanoma progression is tightly associated with the acquisition of genetic and epigenetic alterations in regulators of metabolic pathways. Retinoic acid receptor beta (RARβ) is epigenetically silenced in a large proportion of melanomas, but a link between RARβ and metabolic rewiring of melanoma has not been established. Here, we show that in primary human melanocytes, all-trans retinoic acid (a RARβ agonist) induced growth inhibition accompanied by a decrease in both glycolytic and oxidative metabolism, whereas selective inhibition of RARβ led to an increase in the basal glycolytic rate and increased sensitivity to inhibition of glycolysis...
October 13, 2017: Oncotarget
https://www.readbyqxmd.com/read/29133617/response-and-resistance-to-paradox-breaking-braf-inhibitor-in-melanomas-in-vivo-and-ex-vivo
#3
Edward J Hartsough, Curtis H Kugel, Michael J Vido, Adam C Berger, Timothy J Purwin, Allison Goldberg, Michael A Davies, Matthew J Schiewer, Karen E Knudsen, Gideon Bollag, Andrew E Aplin
FDA-approved BRAF inhibitors produce high response rates and improve overall survival in patients with BRAF V600E/K mutant melanoma, but are linked to pathologies associated with paradoxical ERK1/2 activation in wild-type BRAF cells. To overcome this limitation, a next-generation paradox breaking RAF inhibitor (PLX8394) has been designed. Here we show that by using a quantitative reporter assay, PLX8394 rapidly suppressed ERK1/2 reporter activity and growth of mutant BRAF melanoma xenografts. Ex vivo treatment of xenografts and use of a patient-derived explant system (PDeX) revealed that PLX8394 suppressed ERK1/2 signaling and elicited apoptosis more effectively than the FDA-approved BRAF inhibitor, vemurafenib...
November 13, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29133287/basket-study-yields-approval-for-rare-blood-cancer
#4
(no author information available yet)
The FDA, in a regulatory first, approved a targeted therapy based on a basket study. The move, which expanded the indications for the BRAF inhibitor vemurafenib to include Erdheim-Chester disease, points to a new approval pathway for drugs that treat rare cancers.
November 13, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/29120964/analysis-of-survival-of-patients-treated-with-vemurafenib-ipilimumab-and-dabrafenib-for-advanced-skin-melanoma-in-daily-clinical-practice-real-world-data-retrospective-analysis-of-patients-treated-under-drug-reimbursement-programmes-in-poland-in-2013-2016
#5
Melania Brzozowska, Waldemar Wierzba, Andrzej Śliwczyński, Marcin Świerkowski, Piotr Potemski, Michał Marczak
Vemurafenib, ipilimumab and dabrafenib were registered for the treatment of advanced skin melanoma pursuant to the results of randomized phase III clinical trials. Real-world data on survival time for patients treated with those drugs in daily clinical practice are so far limited. Patients with advanced skin melanoma treated under reimbursement programmes (drug programmes), for which they were qualified pursuant to uniform inclusion criteria in force in all oncology centres in Poland. Data were obtained from the electronic databases of the national payer (NFZ) responsible for the implementation and monitoring of reimbursement (drug) programmes...
November 8, 2017: Melanoma Research
https://www.readbyqxmd.com/read/29117359/co-occurring-genomic-alterations-and-association-with-progression-free-survival-in-brafv600-mutated-nonmelanoma-tumors
#6
Shiraj Sen, Funda Meric-Bernstam, David S Hong, Kenneth R Hess, Vivek Subbiah
BRAFV600 mutations occur in multiple nonmelanoma tumors, but no US Food and Drug Administration-approved BRAF-targeted therapies exist for these cancers. BRAF inhibitor vemurafenib was recently found to demonstrate activity across various BRAF-mutated nonmelanoma cancer types. However, most tumors ultimately become resistant to BRAF-targeted monotherapy. To identify whether co-occurring genomic alterations drive resistance to BRAF-targeted therapies, we analyzed next-generation sequencing data from 30 advanced BRAF-mutated nonmelanoma cancers treated with BRAF inhibitor monotherapy...
October 1, 2017: Journal of the National Cancer Institute
https://www.readbyqxmd.com/read/29113311/the-anti-apoptotic-bag3-protein-is-involved-in-braf-inhibitor-resistance-in-melanoma-cells
#7
Luana Guerriero, Giuseppe Palmieri, Margot De Marco, Antonio Cossu, Paolo Remondelli, Mario Capunzo, Maria Caterina Turco, Alessandra Rosati
BAG3 protein, a member of BAG family of co-chaperones, has a pro-survival role in several tumour types. BAG3 anti-apoptotic properties rely on its characteristic to bind several intracellular partners, thereby modulating crucial events such as apoptosis, differentiation, cell motility, and autophagy. In human melanomas, BAG3 positivity is correlated with the aggressiveness of the tumour cells and can sustain IKK-γ levels, allowing a sustained activation of NF-κB. Furthermore, BAG3 is able to modulate BRAFV600E levels and activity in thyroid carcinomas...
October 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/29112787/dabrafenib-inhibits-the-growth-of-braf-wt-cancers-through-cdk16-and-nek9-inhibition
#8
Manali Phadke, Lily L Remsing Rix, Inna Smalley, Annamarie T Bryant, Yunting Luo, Harshani R Lawrence, Braydon J Schaible, Y Ann Chen, Uwe Rix, Keiran S M Smalley
Although the BRAF inhibitors dabrafenib and vemurafenib have both proven successful against BRAF-mutant melanoma, there seem to be differences in their mechanisms of action. Here, we show that dabrafenib is more effective at inhibiting the growth of NRAS-mutant and KRAS-mutant cancer cell lines than vemurafenib. Using mass spectrometry-based chemical proteomics we identified NEK9 and CDK16 as unique targets of dabrafenib. Both NEK9 and CDK16 were highly expressed in specimens of advanced melanoma, with high expression of both proteins correlating with a worse overall survival...
November 7, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/29103009/metastatic-melanoma-a-rare-cause-of-central-airway-obstruction
#9
Mohamed Faisal Abdul Hamid, Andrea Ban Yu-Lin, Tidi Maharani Hassan, Nurashikin Mohammad
A middle-aged woman with recurrent malignant melanoma presented initially with massive left pleural effusion. There was a complete obliteration of the left main bronchus on flexible bronchoscopy caused by a mass. Serial cryo-debulking of the tumour was done under rigid bronchoscopy; however, the outcome was not favourable due to the aggressive tumour growth. Vemurafenib was planned after thoracic radiation. She was not keen for the biologics treatment due to financial constraints. We report a case of central airway obstruction due to recurrent aggressive melanoma...
November 4, 2017: BMJ Case Reports
https://www.readbyqxmd.com/read/29100713/a-hrm-assay-for-identification-of-low-level-braf-v600e-and-v600k-mutations-using-the-cadma-principle-in-ffpe-specimens
#10
Claudia Huebner, Remeny Weber, Richard Lloydd
Melanoma patients with BRAF V600E and V600K mutations show complete or partial response to vemurafenib. Detection assays often scan for the common V600E mutation rather than the rare V600K variant, although this mutation can be found in a high proportion of melanoma patients in the South Pacific. Herein, we describe a BRAF high resolution melting (HRM) assay that can differentiate low level of V600E and V600K mutations using formalin fixed, paraffin embedded (FFPE) reference standards for assay validation. The assay is based on the competitive amplification of differentially melting amplicons (CADMA principle) and has a limit of detection of 0...
October 31, 2017: Pathology
https://www.readbyqxmd.com/read/29096034/cns-erdheim-chester-disease-a-challenge-to-diagnose
#11
Zenggang Pan, Bette K Kleinschmidt-DeMasters
Erdheim-Chester disease (ECD) is a rare nonLangerhans cell histiocytosis. Although approximately 50% of cases eventually involve the central nervous system (CNS), the CNS has seldom been reported as the initial biopsy site. The diagnosis of CNS ECD can be challenging due to morphologic overlap with reactive histiocytic proliferation, Langerhans cell histiocytosis (LCH), and extranodal Rosai-Dorfman disease (RDD). We present 3 cases from our files that illustrate the protean manifestations of ECD. Case 1 was a 47-year-old man with ataxia, dysarthria, and intermittent ophthalmoplegia whose cerebellar biopsy had shown only profuse, nonspecific Rosenthal fiber-rich piloid gliosis; ECD was diagnosed only at autopsy...
December 1, 2017: Journal of Neuropathology and Experimental Neurology
https://www.readbyqxmd.com/read/29076950/vemurafenib-treatment-for-patients-with-locally-advanced-unresectable-stage-iiic-or-metastatic-melanoma-and-activating-exon-15-braf-mutations-other-than-v600e
#12
Sigrun Hallmeyer, Rene Gonzalez, David H Lawson, Lee D Cranmer, Gerald P Linette, Igor Puzanov, Bret Taback, C Lance Cowey, Antoni Ribas, Gregory A Daniels, Timothy Moore, Geoffrey T Gibney, Hussein Tawbi, Eric Whitman, Geraldine Lee, Yong Mun, Shiyao Liu, Omid Hamid
BRAF mutations are found in ~50% of metastatic melanomas, most commonly in codon V600. Vemurafenib improves progression-free survival and overall survival in patients with advanced BRAF-mutated melanoma. The results of a descriptive study evaluating vemurafenib in patients with advanced melanoma harbouring BRAF mutations other than V600E are reported. Eligible patients with stage IIIC or IV melanoma and non-V600E BRAF mutations received vemurafenib (960 mg, twice daily). End points included investigator-assessed best overall response rate (primary), time to response, duration of response, progression-free survival, overall survival and safety...
December 2017: Melanoma Research
https://www.readbyqxmd.com/read/29075194/pharmacogenomics-dna-biomarkers-in-colorectal-cancer-current-update
#13
REVIEW
Nurul-Syakima Ab Mutalib, Najwa F Md Yusof, Shafina-Nadiawati Abdul, Rahman Jamal
Colorectal cancer (CRC) remains as one of the most common cause of worldwide cancer morbidity and mortality. Improvements in surgical modalities and adjuvant chemotherapy have increased the cure rates in early stage disease, but a significant portion of the patients will develop recurrence or advanced disease. The efficacy of chemotherapy of recurrence and advanced CRC has improved significantly over the last decade. Previously, the historical drug 5-fluorouracil was used as single chemotherapeutic agent. Now with the addition of other drugs such as capecitabine, irinotecan, oxaliplatin, bevacizumab, cetuximab, panitumumab, vemurafenib, and dabrafenib, the median survival of patients with advanced CRC has significantly improved from less than a year to the current standard of almost 2 years...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29064427/the-mek-inhibitors-trametinib-and-cobimetinib-induce-a-type-i-interferon-response-in-human-keratinocytes
#14
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/29059171/suppression-of-rac1-driven-malignant-melanoma-by-group-a-pak-inhibitors
#15
D Araiza-Olivera, Y Feng, G Semenova, T Y Prudnikova, J Rhodes, J Chernoff
Activating mutations in the RAC1 gene have recently been discovered as driver events in malignant melanoma. Expression of this gene is associated with melanocyte proliferation, and melanoma cells bearing this mutation are insensitive to BRAF inhibitors such as vemurafenib and dabrafenib, and also may evade immune surveillance due to enhanced expression of PD-L1. Activating mutations in RAC1 are of special interest, as small-molecule inhibitors for the RAC effector p21-activated kinase (PAK) are in late-stage clinical development and might impede oncogenic signaling from mutant RAC1...
October 23, 2017: Oncogene
https://www.readbyqxmd.com/read/29051322/a-multicenter-phase-i-study-evaluating-dual-pi3k-and-braf-inhibition-with-px-866-and-vemurafenib-in-patients-with-advanced-braf-v600-mutant-solid-tumors
#16
Clinton Yam, Xiaowei Xu, Michael A Davies, Phyllis A Gimotty, Jennifer Jd Morrissette, Michael T Tetzlaff, Khalida Wani, Shujing Liu, Wanleng Deng, Meghan Buckley, Jianhua Zhao, Ravi K Amaravadi, Naomi Haas, Ragini R Kudchadkar, Anna Pavlick, Jeffrey A Sosman, Hussein Tawbi, Luke Walker, Lynn M Schuchter, Giorgos C Karakousis, Tara C Gangadhar
PURPOSE: The objectives of the study were to evaluate the safety of daily oral PX-866 in combination with twice daily vemurafenib and to identify potential predictive biomarkers for this novel combination. EXPERIMENTAL DESIGN: We conducted a phase I, open-label, dose escalation study in patients with advanced BRAF V600 mutant solid tumors. PX-866 was administered on a continuous schedule in combination with vemurafenib. Patients underwent a baseline and on-treatment biopsy after 1-week of PX-866 monotherapy for biomarker assessment...
October 19, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29050239/application-of-in-vivo-imaging-techniques-to-monitor-therapeutic-efficiency-of-plx4720-in-an-experimental-model-of-microsatellite-instable-colorectal-cancer
#17
Sarah Rohde, Tobias Lindner, Stefan Polei, Jan Stenzel, Luise Borufka, Sophie Achilles, Eric Hartmann, Falko Lange, Claudia Maletzki, Michael Linnebacher, Änne Glass, Sarah Marie Schwarzenböck, Jens Kurth, Alexander Hohn, Brigitte Vollmar, Bernd Joachim Krause, Robert Jaster
OBJECTIVES: Patient-derived tumor cell lines are a powerful tool to analyze the sensitivity of individual tumors to specific therapies in mice. An essential prerequisite for such an approach are reliable quantitative techniques to monitor tumor progression in vivo. METHODS: We have employed HROC24 cells, grown heterotopically in NMRI Foxn1(nu) mice, as a model of microsatellite instable colorectal cancer to investigate the therapeutic efficiencies of 5'-fluorouracil (5'-FU) and the mutant BRAF inhibitor PLX4720, a vemurafenib analogue, by three independent methods: external measurement by caliper, magnetic resonance imaging (MRI) and positron emission tomography/computed tomography (PET/CT) with 2-deoxy-2-((18)F)fluoro-D-glucose ((18)F-FDG)...
September 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/29050218/braf-mek-inhibitors-promote-cd47-expression-that-is-reversible-by-erk-inhibition-in-melanoma
#18
Fen Liu, Chen Chen Jiang, Xu Guang Yan, Hsin-Yi Tseng, Chun Yan Wang, Yuan Yuan Zhang, Hamed Yari, Ting La, Margaret Farrelly, Su Tang Guo, Rick F Thorne, Lei Jin, Qi Wang, Xu Dong Zhang
The expression of CD47 on the cancer cell surface transmits "don't eat me" signalling that not only inhibits phagocytosis of cancer cells by phagocytes but also impairs anti-cancer T cell responses. Here we report that oncogenic activation of ERK plays an important role in transcriptional activation of CD47 through nuclear respiratory factor 1 (NRF-1) in melanoma cells. Treatment with BRAF/MEK inhibitors upregulated CD47 in cultured melanoma cells and fresh melanoma isolates. Similarly, melanoma cells selected for resistance to the BRAF inhibitor vemurafenib expressed higher levels of CD47...
September 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/29036262/granuloma-annulare-secondary-to-vemurafenib-therapy-for-lung-adenocarcinoma
#19
Helena A Jenkinson, Alan E Siroy, Adrienne Choksi
Numerous cutaneous manifestations have been associated with use of BRAF inhibitors, including two previously reported cases of granuloma annulare (GA) eruptions associated with vemurafenib therapy. Both of these patients were being treated for metastatic melanoma. In this report, we describe the case of a 71-year-old man who developed classic GA lesions while being treated with vemurafenib monotherapy for nonmelanoma cancer, specifically metastatic lung adenocarcinoma positive for BRAF V600 mutation. <p><em>J Drugs Dermatol...
October 1, 2017: Journal of Drugs in Dermatology: JDD
https://www.readbyqxmd.com/read/29033690/dual-egfr-and-braf-blockade-overcomes-resistance-to-vemurafenib-in-braf-mutated-thyroid-carcinoma-cells
#20
Tiziana Notarangelo, Lorenza Sisinni, Valentina Condelli, Matteo Landriscina
BACKGROUND: BRAF inhibitors are effective anticancer agents in BRAF-mutated melanomas. By contrast, evidences about sensitivity of thyroid carcinomas to BRAF inhibition are conflicting and it has been proposed that BRAF V600E thyroid carcinoma cells are less sensitive to BRAF inhibitors due to activation of parallel signaling pathways. This study evaluated the hypothesis that feedback activation of EGFR signaling counteracts the cytostatic activity of vemurafenib (PLX4032) in BRAF V600E thyroid carcinoma cells...
2017: Cancer Cell International
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