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Dabrafenib

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https://www.readbyqxmd.com/read/28429064/simple-and-cost-effective-liquid-chromatography-mass-spectrometry-method-to-measure-dabrafenib-quantitatively-and-six-metabolites-semi-quantitatively-in-human-plasma
#1
Svante Vikingsson, Jan-Olof Dahlberg, Johan Hansson, Veronica Höiom, Henrik Gréen
Dabrafenib is an inhibitor of BRAF V600E used for treating metastatic melanoma but a majority of patients experience adverse effects. Methods to measure the levels of dabrafenib and major metabolites during treatment are needed to allow development of individualized dosing strategies to reduce the burden of such adverse events. In this study, an LC-MS/MS method capable of measuring dabrafenib quantitatively and six metabolites semi-quantitatively is presented. The method is fully validated with regard to dabrafenib in human plasma in the range 5-5000 ng/mL...
April 20, 2017: Analytical and Bioanalytical Chemistry
https://www.readbyqxmd.com/read/28425764/braf-v600e-mutant-papillary-craniopharyngioma-dramatically-responds-to-combination-braf-and-mek-inhibitors
#2
Ashley Roque, Yazmin Odia
We present a patient with BRAF-V600E mutant papillary craniopharyngioma successfully treated with combination BRAF (dabrafenib 150 mg twice daily) and MEK (trametinib 2 mg daily) inhibitors after her unresectable tumor proved refractory to radiation. Serial brain MRIs and PET revealed marked tumor reduction with gradual neurological improvement and permanent panhypopituitarism.
April 2017: CNS Oncology
https://www.readbyqxmd.com/read/28423638/her-inhibitor-promotes-braf-mek-inhibitor-induced-redifferentiation-in-papillary-thyroid-cancer-harboring-brafv600e
#3
Lingxiao Cheng, Yuchen Jin, Min Liu, Maomei Ruan, Libo Chen
Redifferentiation therapy with BRAF/MEK inhibitors to facilitate treatment with radioiodine represents a good choice for radioiodine-refractory differentiated thyroid carcinoma, but recent initial clinical outcomes were modest. MAPK rebound caused by BRAF/MEK inhibitors-induced activation of HER2/HER3 is a resistance mechanism, and combination with HER inhibitor to prevent MAPK rebound may sensitize BRAFV600E-mutant thyroid cancer cells to redifferentiation therapy. To evaluate if inhibiting both BRAF/MEK and HER can produce stronger redifferetiation effect, we tested the effects of BRAF/MEK inhibitor dabrafenib/selumetinib alone or in combination with HER inhibitor lapatinib on the expression and function of iodine- and glucose-handling genes in BRAFV600E-positive BCPAP and K1 cells, using BHP 2-7 cells harboring RET/PTC1 rearrangement as control...
March 21, 2017: Oncotarget
https://www.readbyqxmd.com/read/28414204/docking-based-structural-splicing-and-reassembly-strategy-to-develop-novel-deazapurine-derivatives-as-potent-b-raf-v600e-inhibitors
#4
Gui-Min Wang, Xiang Wang, Jian-Ming Zhu, Bin-Bin Guo, Zhuo Yang, Zhi-Jian Xu, Bo Li, He-Yao Wang, Ling-Hua Meng, Wei-Liang Zhu, Jian Ding
The mutation of B-Raf(V600E) is widespread in a variety of human cancers. Its inhibitors vemurafenib and dabrafenib have been launched as drugs for treating unresectable melanoma, demonstrating that B-Raf(V600E) is an ideal drug target. This study focused on developing novel B-Raf(V600E) inhibitors as drug leads against various cancers with B-Raf(V600E) mutation. Using molecular modeling approaches, 200 blockbuster drugs were spliced to generate 283 fragments followed by molecular docking to identify potent fragments...
April 17, 2017: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/28412197/an-uplc-ms-ms-method-for-the-quantification-of-braf-inhibitors-vemurafenib-dabrafenib-and-mek-inhibitors-cobimetinib-trametinib-binimetinib-in-human-plasma-application-to-treated-melanoma-patients
#5
Marine Rousset, Karine Titier, Stephane Bouchet, Caroline Dutriaux, Anne Pham-Ledard, Sorilla Prey, Mireille Canal-Raffin, Mathieu Molimard
Targeted therapies for cancers are fast-growing therapies. For instance kinase inhibitors such as BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi) are increasingly used to treat malignant melanoma. The metabolic profile of these drugs can result in great interindividual variability, justifying therapeutic drug monitoring (TDM). We describe a rapid and specific method for quantification of 2 BRAFi (vemurafenib, dabrafenib) and 3 MEKi (cobimetinib, trametinib and binimetinib). Chromatography was performed on a Waters Acquity-UPLC system with CORTECS C18+ column, under a gradient of 10% acetic acid in water/acetonitrile...
April 12, 2017: Clinica Chimica Acta; International Journal of Clinical Chemistry
https://www.readbyqxmd.com/read/28405510/correlation-between-previous-treatment-with-braf-inhibitors-and-clinical-response-to-pembrolizumab-in-patients-with-advanced-melanoma
#6
Ester Simeone, Antonio Maria Grimaldi, Lucia Festino, Diana Giannarelli, Vito Vanella, Marco Palla, Marcello Curvietto, Assunta Esposito, Giuseppe Palmieri, Nicola Mozzillo, Paolo Antonio Ascierto
The optimal sequencing of targeted treatment and immunotherapy in the treatment of advanced melanoma is a key question and prospective studies to address this are ongoing. Previous observations suggest that treating first with targeted therapy may select for more aggressive disease, meaning that patients may not gain full benefit from subsequent immunotherapy. In a single-center retrospective analysis, we investigated whether response to pembrolizumab was affected by previous BRAF inhibitor therapy. A total of 42 patients with metastatic cutaneous or mucosal melanoma who had received previous treatment with ipilimumab were treated with pembrolizumab as part of the Italian expanded access program...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28376479/metastatic-melanoma-treatment-and-survival-in-the-us-after-the-introduction-of-ipilimumab-and-vemurafenib
#7
Lindsey Enewold, Elad Sharon, Linda C Harlan
INTRODUCTION: The 5-year survival of metastatic melanoma is < 18%. Historically, treatment options were limited. In 2011, 2 new agents were approved. METHODS: We re-abstracted the medical records of a random sample (n = 520) of metastatic melanoma patients who had been diagnosed in 2011 and reported to population-based registries in the U.S. We also queried their treating physicians. Factors associated with treatment and survival were assessed using logistic and Cox proportional hazards regressions, respectively...
2017: Oncology Research and Treatment
https://www.readbyqxmd.com/read/28356222/neutrophil-to-lymphocyte-ratio-is-associated-with-outcome-during-ipilimumab-treatment
#8
Michael R Cassidy, Rachel E Wolchok, Junting Zheng, Katherine S Panageas, Jedd D Wolchok, Daniel Coit, Michael A Postow, Charlotte Ariyan
BACKGROUND: Ipilimumab (IPI) and BRAF inhibitors (BRAFi) improve survival in melanoma, but not all patients will benefit and toxicity can be significant. Pretreatment neutrophil to lymphocyte ratio (NLR) has been associated with outcome in IPI-treated patients, but has not been studied during treatment or in BRAFi-treated patients. METHODS: Using a prospectively maintained database, patients with unresectable stage III or IV melanoma treated with IPI or a BRAFi (vemurafenib or dabrafenib as monotherapy) from 2006 to 2011 were identified...
March 24, 2017: EBioMedicine
https://www.readbyqxmd.com/read/28320730/prediction-of-the-transporter-mediated-drug-drug-interaction-potential-of-dabrafenib-and-its-major-circulating-metabolites
#9
Harma Ellens, Marta Johnson, Sarah K Lawrence, Cory A Watson, Liangfu Chen, Lauren E Richards-Peterson
The BRAF inhibitor dabrafenib was recently approved for the treatment of certain BRAF V600 mutation-positive tumors, either alone or in combination therapy with the MEK inhibitor trametinib. This article presents the dabrafenib transporter-mediated drug-drug interaction risk assessment, which is currently an important part of drug development, regulatory submission and drug registration. Dabrafenib and its major circulating metabolites (hydroxy-, carboxy- and desmethyl-dabrafenib) were investigated as inhibitors of the clinically relevant transporters Pgp, BCRP, OATP1B1, OATP1B3, OCT2, OAT1 and OAT3...
March 20, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28303522/nanotechnology-for-the-treatment-of-melanoma-skin-cancer
#10
REVIEW
Lucas B Naves, Chetna Dhand, Jayarama Reddy Venugopal, Lakshminarayanan Rajamani, Seeram Ramakrishna, Luis Almeida
Melanoma is the most aggressive type of skin cancer and has very high rates of mortality. An early stage melanoma can be surgically removed, with a survival rate of 99%. This literature review intends to elucidate the possibilities to treat melanoma skin cancer using hybrid nanofibers developed by advanced electrospinning process. In this review we have shown that the enhanced permeability and retention is the basis for using nanotechnology, aiming topical drug delivery. The importance of the detection of skin cancer in the early stages is directly related to non-metastatic effects and survival rates of melanoma cells...
March 16, 2017: Progress in biomaterials
https://www.readbyqxmd.com/read/28290623/sequential-monitoring-of-pigmented-lesions-during-dabrafenib-treatment-a-prospective-study-and-a-literature-overview
#11
Emi Dika, Martina Lambertini, Pier A Fanti, Bianca M Piraccini, Carlotta Gurioli, Giulia M Ravaioli, Marco A Chessa, Alessandro Traniello Gradassi, Barbara Melotti, Francesca Sperandi, Annalisa Patrizi
BACKGROUND: Targeted therapies in melanoma have shown clinical benefit in incrementing the overall survival of metastatic patients. However, cutaneous adverse events have been frequently associated with these drugs. METHODS: We report our experience in the management of patients treated with dabrafenib for metastatic melanoma, focusing on the monitoring of pigmented lesions. Dermatologic evaluation was performed during the first visit, at the start of each treatment and subsequently after every four weeks...
March 14, 2017: Giornale Italiano di Dermatologia e Venereologia: Organo Ufficiale, Società Italiana di Dermatologia e Sifilografia
https://www.readbyqxmd.com/read/28268064/combination-of-dabrafenib-plus-trametinib-for-braf-and-mek-inhibitor-pretreated-patients-with-advanced-braf-v600-mutant-melanoma-an-open-label-single-arm-dual-centre-phase-2-clinical-trial
#12
Max Schreuer, Yanina Jansen, Simon Planken, Ines Chevolet, Teofila Seremet, Vibeke Kruse, Bart Neyns
BACKGROUND: Patients with BRAF(V600)-mutant melanoma benefit from treatment with the combination of BRAF and MEK inhibitors, but resistance and disease progression develops in most patients. Preclinical studies and case studies have indicated that acquired resistance to BRAF inhibition can be reversible. We aimed to assess the anti-tumour activity of rechallenge with BRAF plus MEK inhibition in a prospective clinical trial. METHODS: In this open-label, single arm, dual-centre, phase 2 academic study in Belgium, patients aged 18 years or older with BRAF(V600)-mutant melanoma who had previously progressed on BRAF inhibitors (with or without MEK inhibitors) and were off-treatment for at least 12 weeks, were treated with dabrafenib 150 mg orally twice per day plus trametinib 2 mg orally once per day...
April 2017: Lancet Oncology
https://www.readbyqxmd.com/read/28263969/activated-mek-cooperates-with-cdkn2a-and-pten-loss-to-promote-the-development-and-maintenance-of-melanoma
#13
H Yang, D A Kircher, K H Kim, A H Grossmann, M W VanBrocklin, S L Holmen, J P Robinson
The development of targeted inhibitors, vemurafenib and dabrafenib, has led to improved clinical outcome for melanoma patients with BRAF(V600E) mutations. Although the initial response to these inhibitors can be dramatic, sometimes causing complete tumor regression, the majority of melanomas eventually become resistant. Mitogen-activated protein kinase kinase (MEK) mutations are found in primary melanomas and frequently reported in BRAF melanomas that develop resistance to targeted therapy; however, melanoma is a molecularly heterogeneous cancer, and which mutations are drivers and which are passengers remains to be determined...
March 6, 2017: Oncogene
https://www.readbyqxmd.com/read/28252479/dabrafenib-plus-trametinib-rechallenge-in-four-melanoma-patients-who-previously-progressed-on-this-combination
#14
Aljosja Rogiers, Pascal Wolter, Oliver Bechter
In unresectable or metastatic melanoma with a BRAF V600 mutation, combined BRAF/MEK targeted therapy improves clinical outcomes. Yet, disease progression because of acquired resistance occurs in the majority of patients. There is emerging evidence that resistance to BRAF-inhibitor-based targeted therapy can be reversible in some cases. We retrospectively analyzed four patients with BRAF-mutant stage IV cutaneous melanoma who were treated with dabrafenib plus trametinib and rechallenged with the same combination after previously experiencing progression...
April 2017: Melanoma Research
https://www.readbyqxmd.com/read/28252478/response-of-braf-inhibitor-associated-squamous-cell-lung-carcinoma-to-drug-withdrawal
#15
Jonathan T Blackmon, Ratika Dhawan, Nina L Terry, Robert M Conry
Vemurafenib and dabrafenib, two Food and Drug Administration-approved selective BRAF kinase inhibitors (BRAFi), have revolutionized the targeted therapy of cutaneous melanoma. Off-target effects of these drugs paradoxically activate the MAP kinase pathway in BRAF wild-type cells, leading to secondary malignancies. Although cutaneous squamous cell carcinomas are by far the most frequent, emergence of potentially life-threatening secondary tumors from other sites following prolonged therapy is a growing concern...
April 2017: Melanoma Research
https://www.readbyqxmd.com/read/28242136/braf-signaling-pathway-inhibition-podocyte-injury-and-nephrotic-syndrome
#16
Luca Perico, Mario Mandalà, Arrigo Schieppati, Camillo Carrara, Paola Rizzo, Sara Conti, Lorena Longaretti, Ariela Benigni, Giuseppe Remuzzi
Dabrafenib and trametinib, BRAF and MEK inhibitors, respectively, are effective targeted metastatic melanoma therapies, but little is known about their nephrotoxicity. Although tubulointerstitial injury has been the most widely reported renal side effect of targeted melanoma therapy, nephrotic syndrome has not been reported before. We report on a patient with metastatic melanoma who developed nephrotic syndrome during dabrafenib and trametinib treatment. Kidney biopsy showed diffuse loss of podocyte cytoarchitecture, extensive foot-process effacement, and glomerular endothelial injury...
February 24, 2017: American Journal of Kidney Diseases: the Official Journal of the National Kidney Foundation
https://www.readbyqxmd.com/read/28194436/real-time-genomic-profiling-of-histiocytoses-identifies-early-kinase-domain-braf-alterations-while-improving-treatment-outcomes
#17
Lynn H Lee, Anjelika Gasilina, Jayeeta Roychoudhury, Jason Clark, Francis X McCormack, Joseph Pressey, Michael S Grimley, Robert Lorsbach, Siraj Ali, Mark Bailey, Philip Stephens, Jeffrey S Ross, Vincent A Miller, Nicolas N Nassar, Ashish R Kumar
Many patients with histiocytic disorders such as Langerhans cell histiocytosis (LCH) or Erdheim-Chester disease (ECD) have treatment-refractory disease or suffer recurrences. Recent findings of gene mutations in histiocytoses have generated options for targeted therapies. We sought to determine the utility of prospective sequencing of select genes to further characterize mutations and identify targeted therapies for patients with histiocytoses. Biopsies of 72 patients with a variety of histiocytoses underwent comprehensive genomic profiling with targeted DNA and RNA sequencing...
February 9, 2017: JCI Insight
https://www.readbyqxmd.com/read/28182109/acute-truncal-lymphedema-secondary-to-axillary-metastatic-melanoma-presenting-like-cellulitis
#18
Shelley J E Hwang, Benjamin Y Kong, Shaun Chou, Deepal Wakade, Matteo S Carlino, Pablo Fernandez-Penas
There are reported cases of diphencyprone used in treating cutaneous metastases of melanoma. Here, we report a patient with previous primary melanoma on his left back treated with surgical excision and lymphadenectomy, followed by radiotherapy for the recurrent tumor on the primary site. Despite radiotherapy and treatment with dabrafenib and trametinib, in-transit metastases have developed and topical diphencyprone was applied to these metastases. Six weeks later, the patient developed fever and a spreading erythematous tender indurated plaque covering the left side of the body including axillae, back, and flank, clinically suggestive of cellulitis...
2017: Case Reports in Medicine
https://www.readbyqxmd.com/read/28177661/anti-inflammatory-effects-of-dabrafenib-in-vitro-and-in-vivo
#19
In-Chul Lee, Jongdoo Kim, Jong-Sup Bae
The screening of bioactive compound libraries can be an effective approach for repositioning FDA-approved drugs or discovering new treatments for human diseases (drug repositioning). Drug repositioning refers to the development of existing drugs for new indications. Dabrafenib (DAB) is a B-Raf inhibitor and initially used for the treatment of metastatic melanoma therapy. Here, we tested the possible use of DAB in the treatment of lipopolysaccharide (LPS)-mediated vascular inflammatory responses. The anti-inflammatory activities of DAB were determined by measuring permeability, neutrophils adhesion and migration, and activation of pro-inflammatory proteins in LPS-activated human umbilical vein endothelial cells (HUVECs) and mice...
February 3, 2017: Canadian Journal of Physiology and Pharmacology
https://www.readbyqxmd.com/read/28151482/critical-role-of-reactive-oxygen-species-ros-for-synergistic-enhancement-of-apoptosis-by-vemurafenib-and-the-potassium-channel-inhibitor-tram-34-in-melanoma-cells
#20
Daniel Bauer, Felix Werth, Ha An Nguyen, Felix Kiecker, Jürgen Eberle
Inhibition of MAP kinase pathways by selective BRAF inhibitors, such as vemurafenib and dabrafenib, have evolved as key therapies of BRAF-mutated melanoma. However, tumor relapse and therapy resistance have remained as major problems, which may be addressed by combination with other pathway inhibitors. Here we identified the potassium channel inhibitor TRAM-34 as highly effective in combination with vemurafenib. Thus apoptosis was significantly enhanced and cell viability was decreased. The combination vemurafenib/TRAM-34 was also effective in vemurafenib-resistant cells, suggesting that acquired resistance may be overcome...
February 2, 2017: Cell Death & Disease
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