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Dabrafenib

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https://www.readbyqxmd.com/read/29326440/braf-inhibition-upregulates-a-variety-of-receptor-tyrosine-kinases-and-their-downstream-effector-gab2-in-colorectal-cancer-cell-lines
#1
Ricarda Herr, Sebastian Halbach, Miriam Heizmann, Hauke Busch, Melanie Boerries, Tilman Brummer
BRAF mutations occur in ~10% of colorectal cancer (CRC) and are associated with poor prognosis. Inhibitors selective for the BRAFV600E oncoprotein, the most common BRAF mutant, elicit only poor response rates in BRAF-mutant CRC as single agents. This unresponsiveness was mechanistically attributed to the loss of negative feedbacks on the epidermal growth factor receptor (EGFR) and initiated clinical trials that combine BRAF (and MEK) inhibitors, either singly or in combination, with the anti-EGFR antibodies cetuximab or panitumumab...
January 12, 2018: Oncogene
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
#2
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/29296640/successful-use-of-dabrafenib-after-the-occurrence-of-drug-rash-with-eosinophilia-and-systemic-symptoms-dress-induced-by-vemurafenib
#3
Camille Pinard, Claire Mignard, Agnès Samain, Anne-Bénédicte Duval-Modeste, Pascal Joly
No abstract text is available yet for this article.
November 2017: JAAD Case Reports
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/29285228/four-month-course-of-adjuvant-dabrafenib-in-patients-with-surgically-resected-stage-iiic-melanoma-characterized-by-a-brafv600e-k-mutation
#5
Parisa Momtaz, James J Harding, Charlotte Ariyan, Daniel G Coit, Taha Merghoub, Billel Gasmi, Daoqi You, Agnes Viale, Katherine S Panageas, Aliaksandra Samoila, Michael A Postow, Jedd D Wolchok, Paul B Chapman
Background: We tested the hypothesis that a 4-month course of adjuvant dabrafenib in stage IIIC BRAF-mutated melanoma would improve 2 year RFS from 24% to 51%, and that tumor-derived cell free DNA (cfDNA) in plasma would correlate with and predict recurrence. Methods: Patients with stage IIIC BRAF V600E/K mutated melanoma who were free of disease after surgical resection received 4 months of adjuvant dabrafenib. Patients were evaluated with imaging at baseline, at the end of cycles 2, 4, 6, then every 3 months until disease relapse or 2 years, whichever came first...
December 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/29243287/evaluation-of-the-effect-of-dabrafenib-and-metabolites-on-qtc-interval-in-patients-with-braf-v600-mutant-tumours
#6
Noelia Nebot, H T Arkenau, Jeffrey R Infante, Jason C Chandler, Andrew Weickhardt, Jason D Lickliter, John Sarantopoulos, Michael S Gordon, Gabriel Mak, Annie St-Pierre, Lihua Tang, Bijoyesh Mookerjee, Stanley W Carson, Siobhan Hayes, Kenneth F Grossmann
AIMS: The effect of repeat oral supratherapeutic dosing of the BRAF inhibitor dabrafenib on QTc interval was assessed in patients with BRAF V600-mutant tumours. METHODS: Part 1 of this phase 1, multicentre, 2-part study (BRF113773/NCT01738451) assessed safety/tolerability of dabrafenib 225 or 300 mg twice daily (BID) to inform part 2 dosing. Patients in part 2 received dabrafenib-matched placebo on day -1, single-dose dabrafenib 300 mg on day 1, 300 mg BID on days 2 to 7, and 300 mg on day 8 (morning), followed by 24-hour Holter electrocardiographic monitoring and pharmacokinetics sample collection each dose day...
December 15, 2017: British Journal of Clinical Pharmacology
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/29235562/targeting-the-raf-kinases-in-human-cancer-the-raf-dimer-dilemma
#8
David E Durrant, Deborah K Morrison
The Raf protein kinases are key intermediates in cellular signal transduction, functioning as direct effectors of the Ras GTPases and as the initiating kinases in the ERK cascade. In human cancer, Raf activity is frequently dysregulated due to mutations in the Raf family member B-Raf or to alterations in upstream Raf regulators, including Ras and receptor tyrosine kinases. First-generation Raf inhibitors, such as vemurafenib and dabrafenib, have yielded dramatic responses in malignant melanomas containing B-Raf mutations; however, their overall usefulness has been limited by both intrinsic and acquired drug resistance...
December 12, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/29222830/dabrafenib-induced-pemphigoid-like-reaction
#9
R Satta, G Onnis, S Gunnella, M A Montesu, A F Agnoletti, E Cozzani
No abstract text is available yet for this article.
December 8, 2017: Clinical and Experimental Dermatology
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
#10
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/29220734/high-throughput-routine-determination-of-17-tyrosine-kinase-inhibitors-by-lc-ms-ms
#11
Camille Merienne, Marine Rousset, Dominique Ducint, Nadège Castaing, Karine Titier, Mathieu Molimard, Stéphane Bouchet
Several studies have shown that therapeutic drug monitoring of tyrosine kinase inhibitors (TKI) can improve their benefit in cancer. An analytical tool has been developed in order to quantify 17 tyrosine kinase inhibitors and 2 metabolites in human plasma (afatinib, axitinib, bosutinib, crizotinib, dabrafenib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, nilotinib, ponatinib, regorafenib, regorafenib M2, regorafenib M5, ruxolitinib, sorafenib, sunitinib, vandetanib). Drugs were arranged in four groups, according to their plasma concentration range: 0...
November 28, 2017: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/29216787/mek-inhibitors-under-development-for-treatment-of-non-small-cell-lung-cancer
#12
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
#13
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/29195664/-actinomycosis-revealed-by-ulceration-of-the-palate-and-gingiva
#14
F Dessirier, J-P Arnault, J Denamps, H Sevestre, C Attencourt, C Lok
BACKGROUND: Actinomycosis is a chronic and extensive granulomatous, bacterial infection. Revelation by oral ulceration is rare. PATIENTS AND METHODS: A 76-year-old patient with diabetes was treated with dabrafenib for stage IV melanoma. A follow-up visit revealed two ulcerated, infiltrated and hyperalgesic lesions of the palate and gingiva. There were no associated signs. The laboratory findings were normal. The possibility of squamous cell carcinoma occurring with BRAF inhibitors was discussed, despite the rarity of such cases in the literature...
November 28, 2017: Annales de Dermatologie et de Vénéréologie
https://www.readbyqxmd.com/read/29171936/braf-internal-deletions-and-resistance-to-braf-mek-inhibitor-therapy
#15
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
#16
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
#17
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
#18
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/29152725/regressed-melanocytic-nevi-secondary-to-pembrolizumab-therapy-an-emerging-melanocytic-dermatologic-effect-from-immune-checkpoint-antibody-blockade
#19
Shakuntala H Mauzo, Michael T Tetzlaff, Kelly Nelson, Rodabe Amaria, Sapna Patel, Phyu P Aung, Priyadharsini Nagarajan, Carlos A Torres-Cabala, Adi Diab, Victor G Prieto, Jonathan L Curry
BACKGROUND: Immune checkpoint antibody blockade is an emerging therapeutic option for treating certain cancers including melanoma. This therapy is associated with dermatologic and systemic toxicities, some of which are more severe than others and may require withholding therapy. CASE REPORTS: We report two patients with melanocytic nevi that regressed with pembrolizumab therapy. The first patient had stage IV BRAF K601E/L584F mutant melanoma that developed a regressed melanocytic nevus while being treated with pembrolizumab...
November 20, 2017: International Journal of Dermatology
https://www.readbyqxmd.com/read/29149136/mapk-pathway-targeted-therapies-care-and-management-of-unique-toxicities-in-patients-with-advanced-melanoma%C3%A2
#20
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
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