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https://www.readbyqxmd.com/read/27909955/suppressive-effects-of-dabrafenib%C3%A2-on-endothelial-protein-c-receptor-shedding
#1
Sae-Kwang Ku, Jongdoo Kim, Sang Chan Kim, Jong-Sup Bae
Beyond its role in the activation of protein C, the endothelial cell protein C receptor (EPCR) plays an important role in the cytoprotective pathway. EPCR can be shed from the cell surface, which is mediated by tumor necrosis factor-α converting enzyme (TACE). Dabrafenib (DAB) is a B-Raf inhibitor and initially used for the treatment of metastatic melanoma therapy. However, little is known about the effects of DAB on EPCR shedding. We investigated this issue by monitoring the effects of DAB on phorbol-12-myristate 13-acetate (PMA)-, tumor necrosis factor (TNF)-α-, interleukin (IL)-1β-induced EPCR shedding in human umbilical vein endothelial cells (HUVECs), and cecal ligation and puncture (CLP)-mediated EPCR shedding in mice and underlying mechanism...
December 1, 2016: Archives of Pharmacal Research
https://www.readbyqxmd.com/read/27905182/optimizing-combination-dabrafenib-and-trametinib-therapy-in-braf-mutation-positive-advanced-melanoma-patients-guidelines-from-australian-melanoma-medical-oncologists
#2
Victoria Atkinson, Georgina V Long, Alexander M Menzies, Grant McArthur, Matteo S Carlino, Michael Millward, Rachel Roberts-Thomson, Benjamin Brady, Richard Kefford, Andrew Haydon, Jonathan Cebon
BRAF mutations occur commonly in metastatic melanomas and inhibition of mutant BRAF and the downstream kinase MEK results in rapid tumor regression and prolonged survival in patients. Combined therapy with BRAF and MEK inhibition improves response rate, progression free survival and overall survival compared with single agent BRAF inhibition, and reduces the skin toxicity that is seen with BRAF inhibitor monotherapy. However, this combination is associated with an increase in other toxicities, particularly drug-related pyrexia, which affects approximately 50% of patients treated with dabrafenib and trametinib (CombiDT)...
December 2016: Asia-Pacific Journal of Clinical Oncology
https://www.readbyqxmd.com/read/27895032/molecular-pathways-receptor-ectodomain-shedding-in-treatment-resistance-and-monitoring-of-cancer
#3
Miles A Miller, Ryan J Sullivan, Douglas A Lauffenburger
Proteases known as sheddases cleave the extracellular domains of their substrates from the cell surface. The A Disintegrin and Metalloproteinases ADAM10 and ADAM17 are among the most prominent sheddases, being widely expressed in many tissues, frequently over-expressed in cancer, and promiscuously cleaving diverse substrates. It is increasingly clear that the proteolytic shedding of transmembrane receptors impacts pathophysiology and drug response. Receptor substrates of sheddases include the cytokine receptors TNFR1 and IL-6R; the Notch receptors; type-I and -III TGF-β receptors; receptor tyrosine kinases (RTKs) such as HER2, HER4, and VEGFR2; and in particular, MET and TAM-family RTKs AXL and Mer (MerTK)...
November 28, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27892777/uveitis-and-papillitis-in-the-setting-of-dabrafenib-and-trametinib-therapy-for-metastatic-melanoma-a-case-report
#4
Jennifer Lim, Anna J Lomax, Catriona McNeil, Brian Harrisberg
PURPOSE: To report the diagnosis of acute VKH-like syndrome as a complication from dabrafenib (a serine/threonine inhibitor of BRAF V600) and trametinib (a MEK inhibitor). In combination, these targeted agents have been shown to prolong overall survival and progression free survival in BRAF mutant metastatic melanoma. METHODS: Retrospective medical chart review including radiologic and ophthalmologic investigations. RESULTS: A patient with metastatic melanoma being treated with dabrafenib and trametinib for 2 months presented with 1 week of visual blurring...
November 28, 2016: Ocular Immunology and Inflammation
https://www.readbyqxmd.com/read/27883956/efficacy-of-braf-inhibitors-in-asian-metastatic-melanoma-patients-potential-implications-of-genomic-sequencing-in-braf-mutated-melanoma
#5
Hee Kyung Kim, Sunyoung Lee, Kyung Kim, Mi Hwa Heo, Hansang Lee, Jinhyun Cho, Nayoung K D Kim, Woongyang Park, Su Jin Lee, Jung Han Kim, Kee-Taek Jang, Sang-Hee Choi, Jeeyun Lee
BACKGROUND: The BRAF inhibitors vemurafenib and dabrafenib are currently the standard treatment for metastatic melanoma with BRAF V600 mutations. However, given the rarity of noncutaneous melanoma, including acral and mucosal subtypes, the efficacy of BRAF inhibitors for this subset of patients has not been extensively investigated. Acquired resistance generally appears 6 to 8 months after treatment with a BRAF inhibitor, and the mechanism of resistance is not well established. METHODS: We examined treatment outcomes for patients diagnosed with metastatic melanoma and treated with BRAF inhibitors at Samsung Medical Center between April 2013 and December 2015...
November 21, 2016: Translational Oncology
https://www.readbyqxmd.com/read/27864013/factors-predictive-of-response-disease-progression-and-overall-survival-after-dabrafenib-and-trametinib-combination-treatment-a-pooled-analysis-of-individual-patient-data-from-randomised-trials
#6
Georgina V Long, Jean-Jacques Grob, Paul Nathan, Antoni Ribas, Caroline Robert, Dirk Schadendorf, Stephen R Lane, Carmen Mak, Philippe Legenne, Keith T Flaherty, Michael A Davies
BACKGROUND: Dabrafenib plus trametinib treatment provides significant benefits over BRAF-inhibitor monotherapy in patients with BRAF(V600E)-mutant or BRAF(V600K)-mutant advanced melanoma; however, in many patients the disease progresses, leading to death. With many treatment options available, understanding clinical factors that predict long-term response and survival for treatments is important for optimisation of patient management. We aimed to identify clinical factors associated with long-term response and survival using pooled data from randomised trials of dabrafenib plus trametinib in patients with metastatic BRAF-mutant melanoma...
November 15, 2016: Lancet Oncology
https://www.readbyqxmd.com/read/27863085/pharmacokinetics-of-dabrafenib-in-a-patient-with-metastatic-melanoma-undergoing-haemodialysis
#7
John J Park, Alan V Boddy, Xiaoman Liu, David Harris, Vincent Lee, Richard F Kefford, Matteo S Carlino
The combination of dabrafenib and trametinib is a standard of care for the management of BRAF mutant metastatic melanoma. Clinical trials excluded patients with end-stage kidney disease (ESKD) and as such no data are available regarding the safety, efficacy and pharmacokinetics of these drugs in such patients. Here, we present the case of a 78 year-old male patient with ESKD managed with haemodialysis (HD), treated with dabrafenib and trametinib at reduced doses. The patient has had a partial response, and this response continues at 9 months since our last follow up without any dose escalation...
November 10, 2016: Pigment Cell & Melanoma Research
https://www.readbyqxmd.com/read/27861609/exploring-molecular-mechanisms-of-paradoxical-activation-in-the-braf-kinase-dimers-atomistic-simulations-of-conformational-dynamics-and-modeling-of-allosteric-communication-networks-and-signaling-pathways
#8
Amanda Tse, Gennady M Verkhivker
The recent studies have revealed that most BRAF inhibitors can paradoxically induce kinase activation by promoting dimerization and enzyme transactivation. Despite rapidly growing number of structural and functional studies about the BRAF dimer complexes, the molecular basis of paradoxical activation phenomenon is poorly understood and remains largely hypothetical. In this work, we have explored the relationships between inhibitor binding, protein dynamics and allosteric signaling in the BRAF dimers using a network-centric approach...
2016: PloS One
https://www.readbyqxmd.com/read/27861317/development-and-validation-of-a-simultaneous-quantification-method-of-fourteen-tyrosine-kinase-inhibitors-in-human-plasma-using-lc-ms-ms
#9
Huu-Hien Huynh, Claire Pressiat, Hélène Sauvageon, Isabelle Madelaine, Patricia Maslanka, Céleste Lebbé, Catherine Thieblemont, Lauriane Goldwirt, Samia Mourah
BACKGROUND: A sensitive LC-MS/MS method for the analysis in a small volume of plasma of 14 tyrosine kinase inhibitors (TKIs) currently used (imatinib, dasatinib, ibrutinib, ponatinib, trametinib, sunitinib, cobimetinib, dabrafenib, erlotinib, lapatinib, nilotinib, bosutinib, sorafenib, and vemurafenib) has been developed and validated. This multi-analyte LC-MS/MS assay is of interest for anticancer drug combination therapy. METHODS: After a simple protein precipitation of plasma samples, the chromatographic separation was performed using a UPLC system coupled with MS/MS in a positive ionization mode...
November 16, 2016: Therapeutic Drug Monitoring
https://www.readbyqxmd.com/read/27830981/recall-radiation-myelitis-after-stereotactic-radiation-and-dabrafenib-in-metastatic-melanoma
#10
Mathilde Weisz Ejlsmark, Charlotte Kristiansen, Jesper Grau Eriksen, Olfred Hansen, Lars Bastholt
No abstract text is available yet for this article.
November 10, 2016: Acta Oncologica
https://www.readbyqxmd.com/read/27815354/cytokine-induced-killer-cells-kill-chemo-surviving-melanoma-cancer-stem-cells
#11
Dario Sangiolo, Loretta Gammaitoni, Lidia Giraudo, Marco Macagno, Valeria Leuci, Giulia Mesiano, Ramona Rotolo, Francesco Sassi, Martina Sanlorenzo, Alessandro Zaccagna, Alberto Pisacane, Rebecca Senetta, Michela Cangemi, Giulia Cattaneo, Valentina Martin, Valentina Coha, Susanna Gallo, Ymera Pignochino, Anna Sapino, Giovanni Grignani, Fabrizio Carnevale-Schianca, Massimo Aglietta
PURPOSE: The MHC-unrestricted activity of cytokine-induced killer (CIK) cells against chemo-surviving melanoma cancer stem cells (mCSCs) was explored, as CSCs are considered responsible for chemo-resistance and relapses. EXPERIMENTAL DESIGN: Putative mCSCs were visualized by engineering patient-derived melanoma cells (MCs) with a lentiviral-vector encoding eGFP under expression control by stemness gene promoter oct4. Their stemness potential was confirmed in vivo by limiting dilution assays...
November 4, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27799506/personalized-treatment-for-a-patient-with-a-braf-v600e-mutation-using-dabrafenib-and-a-tumor-treatment-fields-device-in-a-high-grade-glioma-arising-from-ganglioglioma
#12
Silviya K Meletath, Dean Pavlick, Tim Brennan, Roy Hamilton, Juliann Chmielecki, Julia A Elvin, Norma Palma, Jeffrey S Ross, Vincent A Miller, Philip J Stephens, George Snipes, Veena Rajaram, Siraj M Ali, Isaac Melguizo-Gavilanes
BACKGROUND: Gangliogliomas are slow-growing, low-grade central nervous system tumors affecting children and young adults. However, some patients will experience tumor recurrence and/or malignant progression. This article reports on the clinical history, molecular findings, and treatment response in a patient with BRAF V600-mutated high-grade glioma arising from ganglioglioma. METHODS: Hematoxylin-eosin staining and comprehensive genomic profiling via Foundation One were performed on the tumor sample from a male patient undergoing treatment at the Department of Neuro-Oncology at Baylor University Medical Center...
November 2016: Journal of the National Comprehensive Cancer Network: JNCCN
https://www.readbyqxmd.com/read/27797970/molecular-pathways-maintaining-mapk-inhibitor-sensitivity-by-targeting-nonmutational-tolerance
#13
Michael P Smith, Claudia Wellbrock
Targeting hyperactive MAPK signaling has proven to be an effective treatment for a variety of different cancers. Responses to the BRAF inhibitors vemurafenib and dabrafenib and the MEK inhibitors trametinib and cobimetinib are, however, transient, and complete remission is rarely observed; rather, outgrowth of resistant clones within progressed tumors appears inevitable. These resistant tumors display great heterogeneity, which poses a major challenge to any salvage therapy. Recent focus has, therefore, been on the early dynamics of inhibitor response during tumor regression...
October 19, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27786591/suppression-of-b-raf-v600e-melanoma-cell-survival-by-targeting-mitochondria-using-triphenyl-phosphonium-conjugated-nitroxide-or-ubiquinone
#14
Seung-Keun Hong, Dmytro Starenki, Pui-Kei Wu, Jong-In Park
Most BRAF-mutated melanomas initially responsive to the FDA-approved inhibitors preferentially targeting B-Raf mutated in Val600 residue eventually relapse, requiring additional therapeutic modalities. Recent studies report the significance of metabolic reprograming in mitochondria for maintenance of BRAF-mutated melanomas and for development of their drug resistance to B-Raf inhibitors, providing a rationale for targeting mitochondria as a potential therapeutic strategy for melanoma. We therefore determined whether mitochondria-targeted metabolism-interfering agents can effectively suppress human B-Raf(V600E) melanoma cell lines and their dabrafenib/PLX4032-resistant progenies using mitochondria-targeted carboxy-proxyl (Mito-CP) and ubiquinone (Mito-Q)...
October 27, 2016: Cancer Biology & Therapy
https://www.readbyqxmd.com/read/27781490/dabrafenib-in-brafv600-mutated-anaplastic-pleomorphic-xanthoastrocytoma
#15
Nicholas F Brown, Thomas Carter, Paul Mulholland
Pleomorphic xanthoastrocytoma (PXA) is a rare brain tumor. Anaplastic features are found in 20-30% of cases of PXA and are associated with poor outcomes. Typical treatment is with gross total resection, followed by radiation therapy and cytotoxic chemotherapy at relapse. BRAFV600 mutations have been identified in 38-60% of patients with PXA. Several case reports and small case series have identified clinical benefit with BRAF inhibition in patients with BRAFV600-mutated PXA. We report the second published case of successful treatment with the BRAF inhibitor dabrafenib in a female patient with relapsed anaplastic PXA with a BRAFV600 mutation, and the first published case of dabrafinib treatment following intolerance to vemurafenib...
October 26, 2016: CNS Oncology
https://www.readbyqxmd.com/read/27775948/erythema-nodosum-like-panniculitis-as-a-false-positive-18f-fdg-pet-ct-in-advanced-melanoma-treated-with-dabrafenib-and-trametinib
#16
Isabel Martínez-Rodríguez, Almudena García-Castaño, Remedios Quirce, Julio Jiménez-Bonilla, Ignacio Banzo
We present a 35-year-old woman with left axillary mass. Histopathological analysis revealed metastatic infiltration for BRAF-mutant melanoma. F-FDG PET/CT showed bilateral axillary lymphadenopathy as well as bone and subcutaneous metastases. Dabrafenib (a BRAF inhibitor) and trametinib (a MEK inhibitor) combined therapy was started with a complete metabolic response established by 2 consecutive PET/CT scans. A follow-up PET/CT showed FDG uptake in several subcutaneous nodules in both distal legs, suggesting metastases...
October 21, 2016: Clinical Nuclear Medicine
https://www.readbyqxmd.com/read/27774137/photoinduced-conversion-of-antimelanoma-agent-dabrafenib-to-a-novel-fluorescent-braf-v600e-inhibitor
#17
Boris Pinchuk, Thorsten von Drathen, Viktoria Opel, Christian Peifer
Dabrafenib (Tafinlar) was approved in 2013 by the FDA as a selective single agent treatment for patients with BRAF(V600E) mutation-positive advanced melanoma. One year later, a combination of dabrafenib and trametinib was used for treatment of BRAF(V600E/K) mutant metastatic melanoma. In the present study, we report on hitherto not described photosensitivity of dabrafenib both in organic and aqueous media. The half-lives for dabrafenib degradation were determined. Moreover, we revealed photoinduced chemical conversion of dabrafenib to its planar fluorescent derivative dabrafenib_photo 2...
October 13, 2016: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27770002/triple-therapy-improves-colorectal-cancer-response
#18
(no author information available yet)
Findings from a phase I/II study indicate a higher response rate among patients with BRAF-mutant metastatic colorectal cancer treated with an EGFR inhibitor alongside dual, as opposed to single-level, MAPK blockade. Panitumumab combined with trametinib and dabrafenib only modestly increased median progression-free survival, however; a short-lived decrease in responders' BRAF V600E mutant allele fraction and the emergence of RAS mutations may have been contributing factors.
October 21, 2016: Cancer Discovery
https://www.readbyqxmd.com/read/27759578/tumor-free-osteosclerotic-lesions-in-patients-treated-for-metastatic-melanoma-using-braf-inhibitors
#19
Lea Bottlaender, Marie Perier-Muzet, Véronique Lapras, Luc Thomas, Stephane Dalle
BRAF inhibitors (vemurafenib and dabrafenib) are nowadays commonly prescribed in BRAF-mutant metastatic melanoma and allow improvement of the overall survival and progression-free survival. They are, however, accompanied by many adverse effects which mainly affect the skin. We observed on computed tomographic scans in three different patients after 3 months of treatment, the onset of osteosclerotic lesions. In parallel, the computed tomographic scans showed a significant reduction in all of the previously identified metastases in all patients...
October 18, 2016: Melanoma Research
https://www.readbyqxmd.com/read/27748799/growth-arrest-by-activated-braf-and-mek-inhibition-in-human-anaplastic-thyroid-cancer-cells
#20
Kento Kurata, Naoyoshi Onoda, Satoru Noda, Shinichiro Kashiwagi, Yuka Asano, Kosei Hirakawa, Masaichi Ohira
Anaplastic thyroid cancer (ATC) is a rare malignancy that progresses extremely aggressively and often results in dismal prognosis. We investigated the efficacy of inhibiting the activated RAS/RAF/MEK pathway in ATC cells aiming to clarify the mechanism of effect and resistance. Four human ATC cell lines (ACT-1, OCUT-2, OCUT-4 and OCUT-6) were used. OCUT-4 had a BRAF mutation. OCUT-2 had both BRAF and PI3KCA mutations. ACT-1 and OCUT-6 had wild-type BRAF and NRAS mutations. The effects of dabrafenib, a selective inhibitor of the BRAFV600E kinase, and trametinib, a reversible inhibitor of MEK activity, were investigated...
October 7, 2016: International Journal of Oncology
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