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https://www.readbyqxmd.com/read/29142786/extraordinary-clinical-benefit-to-sequential-treatment-with-targeted-therapy-and-immunotherapy-of-a-braf-v600e-and-pd-l1-positive-metastatic-lung-adenocarcinoma
#1
Shuyu D Li, Annia Martial, Alexa B Schrock, Jane J Liu
Background: The treatment algorithm for metastatic non-small cell lung cancers (NSCLCs) has been evolving rapidly due to the development of new therapeutic agents. Although guidelines are provided by National Comprehensive Cancer Network (NCCN) for treatment options according to biomarker testing results, sequentially applying the three main modalities (chemotherapy, targeted therapy and immunotherapy) remains an ad hoc practice in clinic. In light of recent FDA approval of dabrafenib and trametinib combination for metastatic NSCLCs with BRAF V600E mutation, one question arises due to insufficient clinical data is if the targeted therapy should be used before immunotherapy in patients with both BRAF V600E and PD-L1 expression...
2017: Experimental Hematology & Oncology
https://www.readbyqxmd.com/read/29138474/phagocytosis-of-environmental-or-metabolic-crystalline-particles-induces-cytotoxicity-by-triggering-necroptosis-across-a-broad-range-of-particle-size-and-shape
#2
Mohsen Honarpisheh, Orestes Foresto-Neto, Jyaysi Desai, Stefanie Steiger, Lidia Anguiano Gómez, Bastian Popper, Peter Boor, Hans-Joachim Anders, Shrikant R Mulay
In crystallopathies, crystals or crystalline particles of environmental and metabolic origin deposit within tissues, induce inflammation, injury and cell death and eventually lead to organ-failure. The NLRP3-inflammasome is involved in mediating crystalline particles-induced inflammation, but pathways leading to cell death are still unknown. Here, we have used broad range of intrinsic and extrinsic crystal- or crystalline particle-sizes and shapes, e.g. calcium phosphate, silica, titanium dioxide, cholesterol, calcium oxalate, and monosodium urate...
November 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29127087/dabrafenib-plus-trametinib-is-active-in-braf-v600e-anaplastic-thyroid-cancer
#3
(no author information available yet)
Dual BRAF/MEK inhibition achieves responses in 69% of BRAFV(600E) anaplastic thyroid cancers (ATC).
November 10, 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
#4
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/29112787/dabrafenib-inhibits-the-growth-of-braf-wt-cancers-through-cdk16-and-nek9-inhibition
#5
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/29075194/pharmacogenomics-dna-biomarkers-in-colorectal-cancer-current-update
#6
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/29072975/dabrafenib-and-trametinib-treatment-in-patients-with-locally-advanced-or-metastatic-braf-v600-mutant-anaplastic-thyroid-cancer
#7
Vivek Subbiah, Robert J Kreitman, Zev A Wainberg, Jae Yong Cho, Jan H M Schellens, Jean Charles Soria, Patrick Y Wen, Christoph Zielinski, Maria E Cabanillas, Gladys Urbanowitz, Bijoyesh Mookerjee, Dazhe Wang, Fatima Rangwala, Bhumsuk Keam
Purpose We report the efficacy and safety of dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) combination therapy in BRAF V600E-mutated anaplastic thyroid cancer, a rare, aggressive, and highly lethal malignancy with poor patient outcomes and no systemic therapies with clinical benefit. Methods In this phase II, open-label trial, patients with predefined BRAF V600E-mutated malignancies received dabrafenib 150 mg twice daily and trametinib 2 mg once daily until unacceptable toxicity, disease progression, or death...
October 26, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/29064427/the-mek-inhibitors-trametinib-and-cobimetinib-induce-a-type-i-interferon-response-in-human-keratinocytes
#8
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
#9
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/29057672/chemical-meningitis-related-to-intra-csf-liposomal-cytarabine
#10
B Durand, F Zairi, T Boulanger, J Bonneterre, L Mortier, Emilie Le Rhun
Therapeutic options of leptomeningeal metastases include intra-cerebrospinal fluid (CSF) chemotherapy. Among intra-CSF agents, liposomal cytarabine has advantages but can induce specific toxicities. A BRAF-V600E-mutated melanoma leptomeningeal metastases patient, treated by dabrafenib and liposomal cytarabine, presented after the first injection of liposomal cytarabine with hyperthermia and headaches. Despite sterile CSF/blood analyses, extended intravenous antibiotics were given and the second injection was delayed...
October 23, 2017: CNS Oncology
https://www.readbyqxmd.com/read/29050517/the-safety-and-efficacy-of-dabrafenib-and-trametinib-for-the-treatment-of-melanoma
#11
Sarah Knispel, Lisa Zimmer, Theodora Kanaki, Selma Ugurel, Dirk Schadendorf, Elisabeth Livingstone
The introduction of BRAF and MEK inhibitors into clinical practice improved the prognosis of metastatic melanoma patients. The combination of BRAF inhibitor dabrafenib with MEK inhibitor trametinib has shown its superiority to single agent therapy and is characterized by a tolerable spectrum of adverse events which shows a decrease in incidence over time on treatment. Areas covered: The current scientific literature on safety and adverse events (AEs) related to BRAF and MEK-inhibition has been investigated with special focus on the large phase 3 studies (COMBI-v, COMBI-d and CoBRIM) as well as recent updates presented at oncology and melanoma meetings...
October 20, 2017: Expert Opinion on Drug Safety
https://www.readbyqxmd.com/read/29048639/phenotype-characterization-of-human-melanoma-cells-resistant-to-dabrafenib
#12
Fabiola Gilda Cordaro, Anna Lisa De Presbiteris, Rosa Camerlingo, Nicola Mozzillo, Giuseppe Pirozzi, Ernesta Cavalcanti, Antonella Manca, Giuseppe Palmieri, Antonio Cossu, Gennaro Ciliberto, Paolo A Ascierto, Salvatore Travali, Eduardo J Patriarca, Emilia Caputo
In the present study, the phenotype of melanoma cells resistant to dabrafenib (a B-RAF inhibitor) was investigated, to shed more light on melanoma resistance to B-RAF inhibition. Melanoma cells resistant to dabrafenib were generated using 3 different cell lines, A375, 397 and 624.38, all carrying B-RAFV600E, and they were characterized by cytofluorometric analysis, Ion Torrent technology, immunofluorescence and biochemistry. All dabrafenib-resistant cells showed, in addition to a re-activation of MAPK signaling, morphological changes compared to their sensitive counterparts, accompanied by an increase in CD90 (mesenchymal marker) expression and a decrease in E-cadherin (epithelial marker) expression, suggesting an epithelial-to-mesenchymal-like phenotypic transition...
September 18, 2017: Oncology Reports
https://www.readbyqxmd.com/read/29042256/antiseptic-effects-of-dabrafenib-on-tgfbip-induced-septic-responses
#13
In-Chul Lee, Jong-Sup Bae
Transforming growth factor-β-induced protein (TGFBIp), an extracellular protein, is expressed on several cell types in response to TGF-β stimulation. Human umbilical vein endothelial cell (HUVEC)-derived TGFBIp functions as a mediator of sepsis. Screening of bioactive compound libraries is an effective approach for repositioning FDA-approved drugs or discovering new treatments for human diseases (drug repositioning). Dabrafenib (DAB), a B-Raf inhibitor, was initially used for treating metastatic melanoma...
October 14, 2017: Chemico-biological Interactions
https://www.readbyqxmd.com/read/29040023/dramatic-clinical-and-radiographic-response-to-braf-inhibition-in-a-patient-with-progressive-disseminated-optic-pathway-glioma-refractory-to-mek-inhibition
#14
Abhishek Bavle, Jeremy Jones, Frank Y Lin, Amy Malphrus, Adekunle Adesina, Jack Su
While clinical and radiographic responses to agents targeting the mitogen-activated protein kinases (MAPK) pathway have been repor-ted in pediatric low-grade gliomas (LGG), early phase trials indicate refractoriness to these medications in some of these patients. We report a patient with disseminated LGG with the BRAFV600E mutation, which was refractory to selumetinib, a MEK inhibitor, but subsequently showed immediate clinical and radiographic response to dabrafenib, a BRAF inhibitor, with sustained effect for 9 months prior to clinical progression...
October 17, 2017: Pediatric Hematology and Oncology
https://www.readbyqxmd.com/read/29039591/dabrafenib-in-patients-with-recurrent-braf-v600e-mutated-malignant-glioma-and-leptomeningeal-disease
#15
Michael C Burger, Michael W Ronellenfitsch, Nadja I Lorenz, Marlies Wagner, Martin Voss, David Capper, Theophilos Tzaridis, Ulrich Herrlinger, Joachim P Steinbach, Gabriele Stoffels, Karl-Josef Langen, Christian Brandts, Christian Senft, Patrick N Harter, Oliver Bähr
BRAF V600E mutations occur frequently in malignant melanoma, but are rare in most malignant glioma subtypes. Besides, more benign brain tumors such as ganglioglioma, dysembryoblastic neuroepithelial tumours and supratentorial pilocytic astrocytomas, only pleomorphic xanthoastrocytomas (50-78%) and epitheloid glioblastoma (50%) regularly exhibit BRAF mutations. In the present study, we report on three patients with recurrent malignant gliomas harbouring a BRAF V600E mutation. All patients presented with markedly disseminated leptomeningeal disease at recurrence and had progressed after radiotherapy and alkylating chemotherapy...
October 2, 2017: Oncology Reports
https://www.readbyqxmd.com/read/29026704/therapeutic-inhibitors-against-mutated-braf-and-mek-for-the-treatment-of-metastatic-melanoma
#16
REVIEW
Sunhyo Ryu, Chakyung Youn, Ae Ran Moon, Amanda Howland, Cheryl A Armstrong, Peter I Song
Melanoma is one of the most aggressive cancers in the world and is responsible for the majority of skin cancer deaths. Recent advances in the field of immunotherapy using active, adoptive, and antigen-specific therapeutic approaches, have generated the expectation that these technologies have the potential to improve the treatment of advanced malignancies, including melanoma. Treatment options for metastatic melanoma patients have been dramatically improved by the FDA approval of new therapeutic agents including vemurafenib, dabrafenib, and sorafenib...
September 2017: Chonnam Medical Journal
https://www.readbyqxmd.com/read/28991513/long-term-outcomes-in-patients-with-braf-v600-mutant-metastatic-melanoma-who-received-dabrafenib-combined-with-trametinib
#17
Georgina V Long, Zeynep Eroglu, Jeffrey Infante, Sapna Patel, Adil Daud, Douglas B Johnson, Rene Gonzalez, Richard Kefford, Omid Hamid, Lynn Schuchter, Jonathan Cebon, William Sharfman, Robert McWilliams, Mario Sznol, Suman Redhu, Eduard Gasal, Bijoyesh Mookerjee, Jeffrey Weber, Keith T Flaherty
Purpose To report 5-year landmark analysis efficacy and safety outcomes in patients with BRAF V600-mutant metastatic melanoma (MM) who received BRAF inhibitor dabrafenib (D) and MEK inhibitor trametinib (T) combination therapy versus D monotherapy in the randomized phase II BRF113220 study part C. Patients and Methods BRAF inhibitor-naive patients with BRAF V600-mutant MM were randomly assigned 1:1:1 to receive D 150 mg twice a day, D 150 mg twice a day plus T 1 mg once daily, or D 150 mg twice a day plus T 2 mg once daily (D + T 150/2)...
October 9, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28984291/new-perspectives-for-targeting-raf-kinase-in-human-cancer
#18
REVIEW
Zoi Karoulia, Evripidis Gavathiotis, Poulikos I Poulikakos
The discovery that a subset of human tumours is dependent on mutationally deregulated BRAF kinase intensified the development of RAF inhibitors to be used as potential therapeutics. The US Food and Drug Administration (FDA)-approved second-generation RAF inhibitors vemurafenib and dabrafenib have elicited remarkable responses and improved survival of patients with BRAF-V600E/K melanoma, but their effectiveness is limited by resistance. Beyond melanoma, current clinical RAF inhibitors show modest efficacy when used for colorectal and thyroid BRAF-V600E tumours or for tumours harbouring BRAF alterations other than the V600 mutation...
November 2017: Nature Reviews. Cancer
https://www.readbyqxmd.com/read/28984141/dabrafenib-and-trametinib-in-brafv600e-mutated-glioma
#19
Nicholas F Brown, Thomas Carter, Neil Kitchen, Paul Mulholland
BRAFV600E mutations have been identified in a number of glioma subtypes, most frequently in pleomorphic xanthoastrocytoma, ganglioglioma, pilocytic astrocytoma, and epithelioid glioblastoma. Although the development of BRAF inhibitors has dramatically improved the clinical outcome for patients with BRAFV600E mutant tumors, resistance develops in a majority of patients due to reactivation of the MAPK pathway. Addition of MEK inhibition to BRAF inhibition improves survival. Here we report successful treatment of two patients with BRAFV600E mutant pleomorphic xanthoastrocytoma using the BRAF inhibitor dabrafenib in combination with the MEK inhibitor trametinib...
October 6, 2017: CNS Oncology
https://www.readbyqxmd.com/read/28968566/the-2017-complete-overhaul-of-adjuvant-therapies-for-high-risk-melanoma-and-its-consequences-for-staging-and-management-of-melanoma-patients
#20
Alexander M M Eggermont, Reinhard Dummer
The spectacular outcomes of the phase III trials regarding nivolumab versus ipilimumab in fully resected stage IIIB/C-IV and of the combination of dabrafenib (D) plus trametinib (T) in BRAF-mutant stage III patients demonstrate that effective treatments in advanced melanoma are also highly effective in the adjuvant setting. In 2016, an overall survival benefit with adjuvant high-dose ipilimumab was demonstrated, and the European Organisation for Research and Treatment of Cancer trial 1325 comparing pembrolizumab versus placebo will complete the picture in the early 2018...
September 28, 2017: European Journal of Cancer
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