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https://www.readbyqxmd.com/read/28538872/melanoma-tumor-microenvironment-and-new-treatments
#1
Mara Huffenbaecher Giavina-Bianchi, Pedro Francisco Giavina-Bianchi, Cyro Festa
In the recent past years, many discoveries in the tumor microenvironment have led to changes in the management of melanoma and it is rising up hopes, specially, to those in advanced stages. FDA approved seven new drugs from 2011 to 2014. They are: Vemurafenib, Dabrafenib and Trametinib, kinases inhibitors used for patients that have BRAFV600E mutation; Ipilimumab (anti-CTLA4), Pembrolizumab (anti-PD-1) and Nivolumab (anti-PD-1), monoclonal antibodies that stimulate the immune system; and Peginterferon alfa-2b, an anti-proliferative cytokine used as adjuvant therapy...
March 2017: Anais Brasileiros de Dermatologia
https://www.readbyqxmd.com/read/28537004/mek-inhibitors-in-the-treatment-of-metastatic-melanoma-and-solid-tumors
#2
REVIEW
Antonio M Grimaldi, Ester Simeone, Lucia Festino, Vito Vanella, Martina Strudel, Paolo A Ascierto
The mitogen-activated protein kinase (MAPK) cascade is an intracellular signaling pathway involved in the regulation of cellular proliferation and the survival of tumor cells. Several different mutations, involving BRAF or NRAS, exert an oncogenic effect by activating the MAPK pathway, resulting in an increase in cellular proliferation. These mutations have become targets for new therapeutic strategies in melanoma and other cancers. Selective MEK inhibitors have the ability to inhibit growth and induce cell death in BRAF- and NRAS-mutant melanoma cell lines...
May 23, 2017: American Journal of Clinical Dermatology
https://www.readbyqxmd.com/read/28536078/akt-is-critically-involved-in-the-antagonism-of-braf-inhibitor-sorafenib-against-dabrafenib-in-colorectal-cancer-cells-harboring-both-wild-type-and-mutant-v600e-braf-genes
#3
Hongbin Wang, Haitian Quan, Liguang Lou
BRAF, one of the key factors in mitogen-activated protein kinase (MAPK) signaling pathway, plays an important role in cell functions including growth and proliferation. Inhibition of BRAF represents a promising antitumor strategy. Dabrafenib, a type I inhibitor of BRAF interrupting RAF/MEK interaction, has been approved by FDA as a single agent or combined with MEK inhibitor trametinib for the treatment of patients with BRAF V600E mutation-positive advanced melanoma. In the present study, we investigated the feasibility of combined treatment with dabrafenib and sorafenib, type I and type II BRAF inhibitor respectively, on colorectal cancer cells with BRAF V600E mutation...
May 20, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28526719/management-of-treatment-related-adverse-events-with-agents-targeting-the-mapk-pathway-in-patients-with-metastatic-melanoma
#4
Adil Daud, Katy Tsai
Tremendous progress has been made in the clinical landscape of advanced-stage BRAF V600-mutant melanoma treatment over the past 5 years. Targeted therapies that inhibit specific steps of the mitogen-activated protein kinase pathway have been shown to provide significant overall treatment benefit in patients with this difficult-to-treat disease. Combination therapy with BRAF and MEK inhibitors (dabrafenib plus trametinib or vemurafenib plus cobimetinib, respectively) has become standard of care. These agents are administered until disease progression or unacceptable toxicity occurs; thus, some patients may remain on maintenance therapy for an extended period of time, while toxicities may result in early discontinuation in other patients...
May 18, 2017: Oncologist
https://www.readbyqxmd.com/read/28520456/development-and-validation-of-a-micellar-liquid-chromatographic-method-to-determine-three-antitumorals-in-plasma
#5
Josep Esteve Romero, Jaume Albiol Chiva, Juan Peris-Vicente, Enrique Ochoa-Aranda
AIM: A micellar liquid chromatographic method to determine several anticancer drugs (pazopanib, dabrafenib and regorafenib) in plasma was developed and validated by the guidelines of the EMA. EXPERIMENTAL: Plasma samples were directly injected, after a 1/5-dilution in a micellar solution. The drugs were resolved in <18 min using a C18 column. The mobile phase was an aqueous solution of 0.12 M SDS - 2% 1-pentanol, buffered at pH 7. The detection was performed by absorbance at 260 nm...
May 18, 2017: Bioanalysis
https://www.readbyqxmd.com/read/28500236/identification-of-the-serine-biosynthesis-pathway-as-a-critical-component-of-braf-inhibitor-resistance-of-melanoma-pancreatic-and-non-small-cell-lung-cancer-cells
#6
Kayleigh C Ross, Andrew J Andrews, Christopher D Marion, Timothy J Yen, Vikram Bhattacharjee
Metastatic melanoma cells commonly acquire resistance to BRAF V600E inhibitors (BRAFis). In this study, we identified serine biosynthesis as a critical mechanism of resistance. Proteomic assays revealed differential protein expression of serine biosynthetic enzymes PHGDH, PSPH, and PSAT1 following vemurafenib (BRAFi) treatment in sensitive versus acquired resistant melanoma cells. Ablation of PHGDH via siRNA sensitized acquired resistant cells to vemurafenib. Inhibiting the folate cycle, directly downstream of serine synthesis, with methotrexate also displayed similar sensitization...
May 12, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28480077/combined-dabrafenib-and-trametinib-treatment-in-a-case-of-chemotherapy-refractory-extrahepatic-braf-v600e-mutant-cholangiocarcinoma-dramatic-clinical-and-radiological-response-with-a-confusing-synchronic-new-liver-lesion
#7
Judit Kocsis, Anita Árokszállási, Csilla András, Ingrid Balogh, Edit Béres, Júlia Déri, István Peták, Levente Jánváry, Zsolt Horváth
Since the prognosis of advanced cholangiocarcinoma (CCA) remains poor with traditional chemotherapy, attention has shifted to molecularly targeted agents. Results of available clinical studies reveal little or no benefit of using targeted agents in advanced CCA. Limitations of these trials could be the lack of comprehensive molecular and genetic characterization of CCA samples in order to identify potential drug targets. Here we report a case of a 59-year-old female with chemotherapy-refractor, metastatic extrahepatic cholangiocarcinoma (EHCCA)...
April 2017: Journal of Gastrointestinal Oncology
https://www.readbyqxmd.com/read/28475671/dabrafenib-plus-trametinib-versus-dabrafenib-monotherapy-in-patients-with-metastatic-braf-v600e-k-mutant-melanoma-long-term-survival-and-safety-analysis-of-a-phase-3-study
#8
G V Long, K T Flaherty, D Stroyakovskiy, H Gogas, E Levchenko, F de Braud, J Larkin, C Garbe, T Jouary, A Hauschild, V Chiarion-Sileni, C Lebbe, M Mandalà, M Millward, A Arance, I Bondarenko, J B A G Haanen, J Hansson, J Utikal, V Ferraresi, P Mohr, V Probachai, D Schadendorf, P Nathan, C Robert, A Ribas, M A Davies, S R Lane, J J Legos, B Mookerjee, J-J Grob
Background: Previous analysis of COMBI-d (NCT01584648) demonstrated improved progression-free survival (PFS) and overall survival (OS) with combination dabrafenib and trametinib versus dabrafenib monotherapy in BRAF V600E/K-mutant metastatic melanoma. This study was continued to assess 3-year landmark efficacy and safety after ≥36-month follow-up for all living patients. Patients and methods: This double-blind, phase 3 study enrolled previously untreated patients with BRAF V600E/K-mutant unresectable stage IIIC or stage IV melanoma...
May 5, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
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
#9
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...
June 2017: Analytical and Bioanalytical Chemistry
https://www.readbyqxmd.com/read/28425764/braf-v600e-mutant-papillary-craniopharyngioma-dramatically-responds-to-combination-braf-and-mek-inhibitors
#10
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
#11
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
#12
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
#13
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
#14
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
#15
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
#16
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...
April 2017: EBioMedicine
https://www.readbyqxmd.com/read/28320730/prediction-of-the-transporter-mediated-drug-drug-interaction-potential-of-dabrafenib-and-its-major-circulating-metabolites
#17
Harma Ellens, Marta Johnson, Sarah K Lawrence, Cory 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 mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2 inhibitor, trametinib. This article presents the dabrafenib transporter-mediated drug-drug interaction (DDI) 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 P-gp, BCRP, OATP1B1, OATP1B3, OCT2, OAT1, and OAT3...
June 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28303522/nanotechnology-for-the-treatment-of-melanoma-skin-cancer
#18
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
#19
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
#20
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
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