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https://www.readbyqxmd.com/read/28078189/dabrafenib-and-trametinib-activity-in-a-patient-with-braf-v600e-mutated-and-microsatellite-instability-high-msi-h-metastatic-endometrial-cancer
#1
Michele Moschetta, Gabriel Mak, Joana Hauser, Catriona Davies, Mario Uccello, Hendrik-Tobias Arkenau
BACKGROUND: Targeting BRAF V600E mutation has been proven effective in the treatment of several types of cancer. In endometrial adenocarcinoma, the BRAF V600E mutation has been rarely reported. Whether targeting BRAF oncogene may represent a plausible therapeutic strategy for the rare patients with BRAF-mutated endometrial cancer remains to be ascertained in prospective studies. CASE PRESENTATION: We report herein the case of a heavily pre-treated patient with recurrent microsatellite instability high (MSI-H) BRAF V600E mutated endometrial adenocarcinoma, which was successfully treated with the V600E targeting agent dabrafenib...
2017: Experimental Hematology & Oncology
https://www.readbyqxmd.com/read/28078132/impressive-response-to-dual-braf-and-mek-inhibition-in-patients-with-braf-mutant-intrahepatic-cholangiocarcinoma-2-case-reports-and-a-brief-review
#2
Viraj Lavingia, Marwan Fakih
Intrahepatic cholangiocarcinoma (ICC) typically presents at an advanced stage and is associated with a poor oncological outcome. The median survival for metastatic ICC is less than 1 year with standard chemotherapy. ICC is associated with distinct oncogenic drivers including IDH (isocitrate dehydrogenase), HER-2 (human epidermal growth factor 2), and BRAF (v-Raf murine sarcoma viral oncogene homolog B), which may benefit from matching targeted therapies. Hereby we report 2 cases of BRAF V600E refractory ICC treated with dual BRAF and MEK inhibitors (dabrafenib and trametinib) with excellent clinical and radiological response to therapy and with protracted duration of disease control...
December 2016: Journal of Gastrointestinal Oncology
https://www.readbyqxmd.com/read/28062673/dabrafenib-effective-in-pediatric-glioma
#3
(no author information available yet)
A phase I/II clinical trial suggests that dabrafenib shrinks or stabilizes low-grade gliomas in children with the BRAF V600E mutation. Objective, durable responses occurred in 38% of patients, and the side effects were less severe than with chemotherapy. The researchers have started a second trial for patients with glioma and other BRAF-mutant tumor types, this time evaluating dabrafenib combined with trametinib.
January 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28058658/combination-treatment-of-patients-with-braf-mutant-melanoma-a-new-standard-of-care
#4
REVIEW
Ester Simeone, Antonio M Grimaldi, Lucia Festino, Vito Vanella, Marco Palla, Paolo A Ascierto
Raf-mitogen-activated protein kinase (Raf-MAPK) pathway inhibition with the BRAF inhibitors vemurafenib and dabrafenib, alone or in combination with a MEK inhibitor, has become a standard therapeutic approach in patients with BRAF-mutated metastatic melanoma. Both vemurafenib and dabrafenib have shown good safety and efficacy as monotherapy compared with chemotherapy. However, the duration of response is limited in the majority of patients treated with BRAF inhibitor monotherapy because of the development of acquired resistance...
January 6, 2017: BioDrugs: Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy
https://www.readbyqxmd.com/read/28057719/structure-and-inhibitor-specificity-of-the-pctaire-family-kinase-cdk16
#5
Sarah E Dixon-Clarke, Saifeldin N Shehata, Tobias Krojer, Timothy D Sharpe, Frank von Delft, Kei Sakamoto, Alex N Bullock
CDK16 (also known as PCTAIRE1 or PCTK1) is an atypical member of the cyclin-dependent protein kinase (CDK) family that has emerged as a key regulator of neurite outgrowth, vesicle trafficking and cancer cell proliferation. CDK16 is activated through binding to cyclin Y via a phosphorylation-dependent 14-3-3 interaction and has an unique consensus substrate phosphorylation motif compared to conventional CDKs. To elucidate the structure and inhibitor binding properties of this atypical CDK we screened the CDK16 kinase domain against different inhibitor libraries and determined the co-structures of identified hits...
January 5, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28056412/toxicity-of-concurrent-stereotactic-radiotherapy-and-targeted-therapy-or-immunotherapy-a-systematic-review
#6
REVIEW
Stephanie G C Kroeze, Corinna Fritz, Morten Hoyer, Simon S Lo, Umberto Ricardi, Arjun Sahgal, Rolf Stahel, Roger Stupp, Matthias Guckenberger
BACKGROUND AND PURPOSE: Both stereotactic radiotherapy (SRT) and immune- or targeted therapy play an increasingly important role in personalized treatment of metastatic disease. Concurrent application of both therapies is rapidly expanding in daily clinical practice. In this systematic review we summarize severe toxicity observed after concurrent treatment. MATERIAL AND METHODS: PubMed and EMBASE databases were searched for English literature published up to April 2016 using keywords "radiosurgery", "local ablative therapy", "gamma knife" and "stereotactic", combined with "bevacizumab", "cetuximab", "crizotinib", "erlotinib", "gefitinib", "ipilimumab", "lapatinib", "sorafenib", "sunitinib", "trastuzumab", "vemurafenib", "PLX4032", "panitumumab", "nivolumab", "pembrolizumab", "alectinib", "ceritinib", "dabrafenib", "trametinib", "BRAF", "TKI", "MEK", "PD1", "EGFR", "CTLA-4" or "ALK"...
December 19, 2016: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/28052762/indirect-treatment-comparison-of-dabrafenib-plus-trametinib-versus-vemurafenib-plus-cobimetinib-in-previously-untreated-metastatic-melanoma-patients
#7
Adil Daud, Japinder Gill, Sheily Kamra, Lei Chen, Amit Ahuja
BACKGROUND: Metastatic melanoma is an aggressive form of skin cancer with a high mortality rate and the fastest growing global incidence rate of all malignancies. The introduction of BRAF/MEK inhibitor combinations has yielded significant increases in PFS and OS for melanoma. However, at present, no direct comparisons between different BRAF/MEK combinations have been conducted. In light of this, an indirect treatment comparison was performed between two BRAF/MEK inhibitor combination therapies for metastatic melanoma, dabrafenib plus trametinib and vemurafenib plus cobimetinib, in order to understand the relative efficacy and toxicity profiles of these therapies...
January 4, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28024926/durable-response-to-combination-of-dabrafenib-and-trametinib-in-braf-v600e-mutated-non-small-cell-lung-cancer
#8
Leah M Pervere, Sagar Rakshit, Alexa B Schrock, Vincent A Miller, Siraj M Ali, Vamsidhar Velcheti
No abstract text is available yet for this article.
November 11, 2016: Clinical Lung Cancer
https://www.readbyqxmd.com/read/28005274/neutrophilic-eccrine-hidradenitis-in-2-patients-treated-with-braf-inhibitors-a-new-cutaneous-adverse-event
#9
F Herms, N Franck, N Kramkimel, F Fichel, L Delaval, S Laurent-Roussel, A Carlotti, M-F Avril
Neutrophilic eccrine hidradenitis (NEH) is a rare neutrophilic dermatosis, first described in patients undergoing chemotherapy for a malignant hemopathy. Clinical features are polymorphous. Association of clinical and histological features are necessary to make a diagnosis. We report the first two cases of NEH in patients treated with a BRAF inhibitor (BRAFi), either dabrafenib or vemurafenib, for a stage IV metastatic melanoma. Disseminated erythematous plaques associated with fever and polyarthralgia occurred early after initiation of treatment and were badly tolerated...
December 22, 2016: British Journal of Dermatology
https://www.readbyqxmd.com/read/27973971/bilateral-ischemic-retinal-vasculitis-in-metastatic-cutaneous-melanoma-patient-treated-with-dabrafenib-and-trametinib-a-case-report
#10
Alfredo Niro, Nicola Recchimurzo, Alessandra Sborgia, Michele Guida, Giovanni Alessio
No abstract text is available yet for this article.
December 14, 2016: Ocular Immunology and Inflammation
https://www.readbyqxmd.com/read/27956260/allosteric-mek1-2-inhibitors-including-cobimetanib-and-trametinib-in-the-treatment-of-cutaneous-melanomas
#11
REVIEW
Robert Roskoski
The Ras-Raf-MEK-ERK (Map kinase) cellular pathway is a highly conserved eukaryotic signaling module that transduces extracellular signals from growth factors and cytokines into intracellular regulatory events that are involved in cell growth and proliferation or the contrary pathway of cell differentiation. Dysregulation of this pathway occurs in more than one-third of all malignancies, a process that has fostered the development of targeted Map kinase pathway inhibitors. Cutaneous melanomas, which arise from skin melanocytes, are the most aggressive form of skin cancer...
December 9, 2016: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/27940476/trametinib-following-disease-reactivation-under-dabrafenib-in-erdheim-chester-disease-with-both-braf-and-kras-mutations
#12
Thierry M Nordmann, Freimut D Juengling, Mike Recher, Christoph T Berger, Daniel Kalbermatten, Andreas Wicki, Aino Paasinen-Sohns, Gieri Cathomas, Alexandar Tzankov, Thomas Daikeler
Major advances have been made in understanding the pathogenesis of Erdheim-Chester disease (ECD) leading to novel treatment strategies. Targeted therapies such as BRAF inhibition have shown a significant impact on disease management, emphasizing the importance of the activated mitogen-associated protein kinase (MAPK) pathway in this disease. However, incomplete responsiveness, potentially limiting side effects and the occurrence of treatment resistance to BRAF inhibition observed in other BRAF mutant malignancies imply the importance of therapeutic strategies beyond BRAF inhibition...
December 9, 2016: Blood
https://www.readbyqxmd.com/read/27934295/activity-based-protein-profiling-shows-heterogeneous-signaling-adaptations-to-braf-inhibition
#13
Ritin Sharma, Inna Fedorenko, Paige T Spence, Vernon K Sondak, Keiran S M Smalley, John M Koomen
Patients with BRAF V600E mutant melanoma are typically treated with targeted BRAF kinase inhibitors, such as vemurafenib and dabrafenib. Although these drugs are initially effective, they are not curative. Most of the focus to date has been upon genetic mechanisms of acquired resistance; therefore, we must better understand the global signaling adaptations that mediate escape from BRAF inhibition. In the current study, we have used activity-based protein profiling (ABPP) with ATP-analogue probes to enrich kinases and other enzyme classes that contribute to BRAF inhibitor (BRAFi) resistance in four paired isogenic BRAFi-naïve/resistant cell line models...
December 2, 2016: Journal of Proteome Research
https://www.readbyqxmd.com/read/27909955/suppressive-effects-of-dabrafenib%C3%A2-on-endothelial-protein-c-receptor-shedding
#14
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
#15
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
#16
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
#17
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
#18
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...
December 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
#19
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...
December 2016: Lancet Oncology
https://www.readbyqxmd.com/read/27863085/pharmacokinetics-of-dabrafenib-in-a-patient-with-metastatic-melanoma-undergoing-haemodialysis
#20
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
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