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Braf mek

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
Marta Polkowska, Edyta Czepielewska, Małgorzata Kozłowska-Wojciechowska
Advanced melanoma is related to a very grim prognosis and fast progression. Until recently, there has been no indicated treatment that would affect the disease's outcome. However, the progress in immunotherapy and molecular therapy has significantly changed the unfavourable prognosis of melanoma progression and its short survival rate. Both approaches have improved patients' outcomes and provided renewed hope for successful treatment. Moreover, in order to further enhance patients' outcomes and to avoid mechanisms of tumour resistance, investigators attempted a combined approach...
December 2016: Current Treatment Options in Oncology
Hisato Kawakami, Shengbing Huang, Krishnendu Pal, Shamit K Dutta, Debabrata Mukhopadhyay, Frank A Sinicrope
Oncogenic BRAFV600E mutations activate MAP kinase signaling and are associated with treatment resistance and poor prognosis in patients with colorectal cancer (CRC). In BRAFV600E mutant CRCs, treatment failure may be related to BRAFV600E -mediated apoptosis resistance that occurs by an as yet undefined mechanism. We found that BRAFV600E can upregulate anti-apoptotic MCL-1 in a gene dose-dependent manner using CRC cell lines isogenic for BRAF. BRAFV600E -induced MCL-1 upregulation was confirmed by ectopic BRAFV600E expression that activated MEK/ERK signaling to phosphorylate (MCL-1Thr163) and stabilize MCL-1...
October 7, 2016: Molecular Cancer Therapeutics
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
Jun Gong, May Cho, Marwan Fakih
The treatment of metastatic colorectal cancer (mCRC) has been further refined with the development of monoclonal antibodies, cetuximab and panitumumab, towards the epidermal growth factor receptor (EGFR). Anti-EGFR therapy has afforded improved survival in those with wild-type RAS mCRC but provides no benefit and even harm in those with RAS-mutant tumors. BRAF mutations have also been shown to predict lack of clinically meaningful benefit to anti-EGFR therapy in mCRC. Mechanisms of resistance to EGFR blockade in wild-type RAS or BRAF metastatic colorectal tumors appear to converge on the mitogen-activated protein kinase (MAPK) signaling pathway...
October 2016: Journal of Gastrointestinal Oncology
Young Hak Kim
No abstract text is available yet for this article.
September 2016: Journal of Thoracic Disease
Rikhia Chakraborty, Thomas M Burke, Oliver A Hampton, Daniel J Zinn, Karen Phaik Har Lim, Harshal Abhyankar, Brooks Scull, Vijetha Kumar, Nipun Kakkar, David A Wheeler, Angshumoy Roy, Poulikos I Poulikakos, Miriam Merad, Kenneth L McClain, D Williams Parsons, Carl E Allen
Langerhans cell histiocytosis (LCH) is characterized by inflammatory lesions containing pathologic CD207+ dendritic cells with constitutively activated ERK. Mutually exclusive somatic mutations in MAPK pathway genes have been identified in approximately 75% of LCH cases, including recurrent BRAF-V600E and MAP2K1 mutations. In order to elucidate mechanisms of ERK activation in the remaining 25% of patients, we performed whole exome sequencing (WES, n=6), targeted BRAF sequencing (n=19) and/or whole transcriptome sequencing (RNA-seq, n=6) on 24 LCH patient samples lacking BRAF-V600E or MAP2K1 mutations...
October 11, 2016: Blood
Matteo S Carlino, Vito Vanella, Christina Girgis, Diana Giannarelli, Alex Guminski, Lucia Festino, Richard F Kefford, Alexander M Menzies, Georgina V Long, Paolo A Ascierto
BACKGROUND: It is unknown whether melanoma patients achieving complete response (CR) with targeted therapy can safely discontinue treatment. METHODS: All patients treated with BRAF/MEK inhibitors achieving CR and ceasing treatment before progression were identified. Clinical data at treatment initiation, cessation and progression were examined. RESULTS: A total of 12 eligible patients were identified, with median follow-up of 16 months, of whom 6 (50%) recurred at a median of 6...
October 6, 2016: British Journal of Cancer
Markus V Heppt, Cecilia Dietrich, Saskia A Graf, Thomas Ruzicka, Julia K Tietze, Carola Berking
Melanoma is a common type of skin cancer with a high propensity to metastasize. Tyrosine kinase inhibitors targeting the mitogen-activated protein kinase (MAPK) pathway and immune checkpoint blockade have recently revolutionized the management of unresectable and metastatic disease. However, acquired resistance and primary non-response to therapy require novel treatment strategies and combinations. The purpose of this review is to provide a brief and up-to-date overview on the clinical management and current trial landscape in melanoma...
2016: Oncology Research and Treatment
Jessie Signorelli, Arpita Shah Gandhi
OBJECTIVE: To review and summarize data on cobimetinib, which was approved by the US Food and Drug Administration (FDA) in November 2015 for use in combination with vemurafenib for unresectable or metastatic melanoma with a BRAFV600E or V600K mutation. DATA SOURCES: A literature search using PubMed was conducted using the terms cobimetinib, MEK inhibitor, and melanoma from January 2000 to June 2016. STUDY SELECTION AND DATA EXTRACTION: The literature search was confined to human studies published in English...
October 3, 2016: Annals of Pharmacotherapy
Ana Cebollero, Teresa Puértolas, Isabel Pajares, Lourdes Calera, Antonio Antón
A retrospective observational study was conducted on patients diagnosed with serine/threonine-protein kinase B-Raf (BRAF)-mutated metastatic melanoma, who underwent first-line therapy with BRAF and mitogen-activated protein kinase kinase (MEK) inhibitors (vemurafenib, dabrafenib or a combination of dabrafenib and trametinib) at the Miguel Servet University Hospital (Zaragoza, Spain) between November, 2011 and August, 2015. The aim of this study was to analyse the toxicity produced by BRAF and MEK inhibitors...
October 2016: Molecular and Clinical Oncology
Rishi Agarwal, Jiang Wang, Keith Wilson, William Barrett, John C Morris
Anaplastic thyroid cancer (ATC) is an aggressive uncommon malignancy with limited treatment. Traditional antineoplastic chemotherapy has not been successful in the management of metastatic ATC. As a result, the focus has shifted to the development of novel therapies for this disease. The availability of economical comprehensive genomic profiling (CGP) platforms with rapid turn-around to identify molecular aberrations in tumors that are potential therapeutic targets has increasingly changed the face of cancer therapy...
October 2016: Journal of the National Comprehensive Cancer Network: JNCCN
Kei Kawaguchi, Takashi Murakami, Bartosz Chmielowski, Kentaro Igarashi, Tasuku Kiyuna, Michiaki Unno, Scott D Nelson, Tara A Russell, Sarah M Dry, Yunfeng Li, Fritz C Eilber, Robert M Hoffman
Melanoma is a recalcitrant disease. The present study used a patient-derived orthotopic xenograft (PDOX) model of melanoma to test sensitivity to three molecularly-targeted drugs and one standard chemotherapeutic. A BRAF-V600E-mutant melanoma obtained from the right chest wall of a patient was grown orthotopically in the right chest wall of nude mice to establish a PDOX model. Two weeks after implantation, 50 PDOX nude mice were divided into 5 groups: G1, control without treatment; G2, vemurafenib (VEM) (30 mg/kg); G3; temozolomide (TEM) (25 mg/kg); G4, trametinib (TRA) (0...
September 28, 2016: Oncotarget
M Echevarria, K A Ahmed, B Patel, Y A Abuodeh, A O Naghavi, S Sarangkasiri, P A S Johnstone, A B Etame, H M Yu
No abstract text is available yet for this article.
October 1, 2016: International Journal of Radiation Oncology, Biology, Physics
James Nagarajah, Mina Le, Jeffrey A Knauf, Giuseppe Ferrandino, Cristina Montero-Conde, Nagavarakishore Pillarsetty, Alexander Bolaender, Christopher Irwin, Gnana Prakasam Krishnamoorthy, Mahesh Saqcena, Steven M Larson, Alan L Ho, Venkatraman Seshan, Nobuya Ishii, Nancy Carrasco, Neal Rosen, Wolfgang A Weber, James A Fagin
Radioiodide (RAI) therapy of thyroid cancer exploits the relatively selective ability of thyroid cells to transport and accumulate iodide. Iodide uptake requires expression of critical genes that are involved in various steps of thyroid hormone biosynthesis. ERK signaling, which is markedly increased in thyroid cancer cells driven by oncogenic BRAF, represses the genetic program that enables iodide transport. Here, we determined that a critical threshold for inhibition of MAPK signaling is required to optimally restore expression of thyroid differentiation genes in thyroid cells and in mice with BrafV600E-induced thyroid cancer...
September 26, 2016: Journal of Clinical Investigation
Catherine E Bond, Diane M McKeone, Murugan Kalimutho, Mark L Bettington, Sally-Ann Pearson, Troy D Dumenil, Leesa F Wockner, Matthew Burge, Barbara A Leggett, Vicki L J Whitehall
Serrated pathway colorectal cancers (CRCs) are characterised by a BRAF mutation and half display microsatellite instability (MSI). The Wnt pathway is commonly upregulated in conventional CRC through APC mutation. By contrast, serrated cancers do not mutate APC. We investigated mutation of the ubiquitin ligases RNF43 and ZNRF3 as alternate mechanism of altering the Wnt signal in serrated colorectal neoplasia. RNF43 was mutated in 47/54(87%) BRAF mutant/MSI and 8/33(24%) BRAF mutant/microsatellite stable cancers compared to only 3/79(4%) BRAF wildtype cancers (p<0...
September 20, 2016: Oncotarget
Alex A Adjei, Patricia LoRusso, Antoni Ribas, Jeffrey A Sosman, Anna Pavlick, Grace K Dy, Xiaofei Zhou, Esha Gangolli, Michelle Kneissl, Stephanie Faucette, Rachel Neuwirth, Viviana Bózon
Purpose TAK-733, an investigational, selective, allosteric MEK1/2 inhibitor, has demonstrated antitumor effects against multiple cancer cell lines and xenograft models. This first-in-human study investigated TAK-733 in patients with solid tumors. Methods Patients received oral TAK-733 once daily on days 1-21 in 28-day treatment cycles. Adverse events (AEs) were graded using the Common Terminology Criteria for AEs version 3.0. Response was assessed using RECIST v1.1. Blood samples for TAK-733 pharmacokinetics and pharmacodynamics (inhibition of ERK phosphorylation) were collected during cycle 1...
September 21, 2016: Investigational New Drugs
S J E Hwang, R Anforth, G Carlos, P Fernandez-Peñas
Over the past decade, targeted therapies such as BRAF inhibitors, MEK inhibitors and immunotherapies such as anti-CTLA4 and anti-PD1 antibodies have emerged as novel treatments of advanced melanoma. Along with increased use of these therapies, a range of cutaneous adverse events have also emerged, varying from more serious and frequent cutaneous squamous cell carcinoma to mere cosmetic changes such as curly hair or rare severe toxic epidermal necrolysis. Early detection and management of these cutaneous adverse events will aid patients to receive accurate treatment, avoid unnecessary discontinuation of anti-tumour treatment and improve the patient's overall quality of life...
September 15, 2016: Actas Dermo-sifiliográficas
Ulrich J M Mey, Christoph Renner, Roger von Moos
BRAF mutations are present in a variety of cancers and cause constitutive activation of the Ras-Raf-MEK-ERK signaling pathway. In cutaneous malignant melanoma, combined treatment with BRAF and MEK inhibitors is associated with high response rates and has been shown to improve progression free as well as overall survival compared to BRAF inhibition alone. In multiple myeloma, BRAF mutations are detectable only in a minority of patients. Only few data are available regarding the clinical activity of BRAF inhibitors in BRAF-positive multiple myeloma patients, including some anecdotal reports on remarkable responses in individuals being resistant to all other available anti-myeloma treatment approaches...
September 19, 2016: Hematological Oncology
K A Ahmed, Y A Abuodeh, M I Echevarria, J A Arrington, D G Stallworth, C Hogue, A O Naghavi, S Kim, Y Kim, B G Patel, S Sarangkasiri, P A S Johnstone, S Sahebjam, N I Khushalani, P A Forsyth, L B Harrison, M Yu, A B Etame, J J Caudell
BACKGROUND: The effect of immunologic and targeted agents on intracranial response rates in patients with melanoma brain metastases (MBMs) is not yet clearly understood. This report analyzes outcomes of intact MBMs treated with single-session stereotactic radiosurgery (SRS) and anti-PD-1 therapy, anti-CTLA-4 therapy, BRAF/MEK inhibitors(i), BRAFi, or conventional chemotherapy. PATIENTS AND METHODS: Patients were included if MBMs were treated with single-session SRS within 3 months of receiving systemic therapy...
September 15, 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
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