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Trametinib

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https://www.readbyqxmd.com/read/28441383/the-oral-vegf-receptor-tyrosine-kinase-inhibitor-pazopanib-in-combination-with-the-mek-inhibitor-trametinib-in-advanced-cholangiocarcinoma
#1
Rachna T Shroff, Mark Yarchoan, Ashley O'Connor, Denise Gallagher, Marianna L Zahurak, Gary Rosner, Chimela Ohaji, Susan Sartorius-Mergenthaler, Vivek Subbiah, Ralph Zinner, Nilofer S Azad
BACKGROUND: Cholangiocarcinoma is an aggressive malignancy with limited therapeutic options. MEK inhibition and antiangiogenic therapies have individually shown modest activity in advanced cholangiocarcinoma, whereas dual inhibition of these pathways has not been previously evaluated. We evaluated the safety and efficacy of combination therapy with the oral VEGF receptor tyrosine kinase inhibitor pazopanib plus the MEK inhibitor trametinib in patients with advanced cholangiocarcinoma...
April 25, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/28439535/a-murine-preclinical-syngeneic-transplantation-model-for-breast-cancer-precision-medicine
#2
Lorenzo Federico, Zechen Chong, Dong Zhang, Daniel J McGrail, Wei Zhao, Kang Jin Jeong, Christopher P Vellano, Zhenlin Ju, Mihai Gagea, Shuying Liu, Shreya Mitra, Jennifer B Dennison, Philip L Lorenzi, Robert Cardnell, Lixia Diao, Jing Wang, Yiling Lu, Lauren A Byers, Charles M Perou, Shiaw-Yih Lin, Gordon B Mills
We previously demonstrated that altered activity of lysophosphatidic acid in murine mammary glands promotes tumorigenesis. We have now established and characterized a heterogeneous collection of mouse-derived syngeneic transplants (MDSTs) as preclinical platforms for the assessment of personalized pharmacological therapies. Detailed molecular and phenotypic analyses revealed that MDSTs are the most heterogeneous group of genetically engineered mouse models (GEMMs) of breast cancer yet observed. Response of MDSTs to trametinib, a mitogen-activated protein kinase (MAPK) kinase inhibitor, correlated with RAS/MAPK signaling activity, as expected from studies in xenografts and clinical trials providing validation of the utility of the model...
April 2017: Science Advances
https://www.readbyqxmd.com/read/28433687/steroid-resistance-of-airway-type-2-innate-lymphoid-cells-ilc2s-from-severe-asthma-the-role-of-thymic-stromal-cell-lymphopoietin-tslp
#3
Sucai Liu, Mukesh Verma, Lidia Michalec, Weimin Liu, Anand Sripada, Donald Rollins, James Good, Yoko Ito, HongWei Chu, Magdalena M Gorska, Richard J Martin, Rafeul Alam
BACKGROUND: ILC2s represent an important type 2 immune cell. Glucocorticoid regulation of human ILC2s is largely unknown. OBJECTIVE: To assess steroid resistance of human blood and airway ILC2s from asthmatic patients and examine its mechanism of induction. METHODS: We studied human blood and lung ILC2s from asthmatic and control subjects by flow cytometry and ELISA. RESULTS: Dexamethasone (Dex) inhibited (P=0.04) CRTH2 and type 2 cytokine expression by blood ILC2s stimulated with IL25 and IL33...
April 19, 2017: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/28425764/braf-v600e-mutant-papillary-craniopharyngioma-dramatically-responds-to-combination-braf-and-mek-inhibitors
#4
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/28422736/identification-of-map-kinase-pathways-as-therapeutic-targets-in-gallbladder-carcinoma-using-targeted-parallel-sequencing
#5
Mengdan Li, Lihong Chen, Yiping Qu, Fang Sui, Qi Yang, Meiju Ji, Bingyin Shi, Mingwei Chen, Peng Hou
The aim of this study was to profile somatic mutation spectrum in gallbladder cancers (GBCs), and determine the role of MAP kinase pathway in GBC by a series of in vitro and in vivo studies. We performed targeted massively parallel sequencing of DNA isolated from GBCs and matched blood from 14 GBC patients to search for mutations in 504 genes commonly altered in human cancers. We identified recurrent mutations enriched in several major signaling pathways including MAP kinase, Wnt/β-catenin and NF-κB pathways...
March 31, 2017: Oncotarget
https://www.readbyqxmd.com/read/28415756/human-melanoma-cells-resistant-to-mapk-inhibitors-can-be-effectively-targeted-by-inhibition-of-the-p90-ribosomal-s6-kinase
#6
Corinna Kosnopfel, Tobias Sinnberg, Birgit Sauer, Heike Niessner, Anja Schmitt, Elena Makino, Andrea Forschner, Stephan Hailfinger, Claus Garbe, Birgit Schittek
The clinical availability of small molecule inhibitors specifically targeting mutated BRAF marked a significant breakthrough in melanoma therapy. Despite a dramatic anti-tumour activity and improved patient survival, rapidly emerging resistance, however, greatly limits the clinical benefit. The majority of the already described resistance mechanisms involve a reactivation of the MAPK signalling pathway. The p90 ribosomal S6 kinase (RSK), a downstream effector of the MAPK signalling cascade, has been reported to enhance survival of melanoma cells in response to chemotherapy...
March 15, 2017: Oncotarget
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
#7
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/28388658/the-prognostic-significance-of-dapk1-in-bladder-cancer
#8
Jian-Yun Xie, Peng-Chen Chen, Jia-Li Zhang, Ze-Shou Gao, Henrique Neves, Shu-Dong Zhang, Qing Wen, Wei-Dong Chen, Hang Fai Kwok, Yao Lin
Bladder cancer is one of the leading causes of cancer-related death in men, however, there was only limited effective treatment for invasive bladder cancer. DAPK1 has been shown to play important role in apoptosis and autophagy to suppress cancer progression. Previous results have shown that DAPK1 promoter was hypermethylated in the majority of bladder cancer specimens, however, the prognostic significance of DAPK1 in bladder cancer has yet to be demonstrated. In the present study, we found that DAPK1 expression was negatively associated with tumor stage and a low level expression of DAPK1 in bladder cancer specimens were associated with shorter survival in bladder cancer patients in 3 independent bladder cancer datasets (n = 462)...
2017: PloS One
https://www.readbyqxmd.com/read/28377484/phase-ib-ii-study-of-safety-efficacy-of-combination-therapy-with-multikinase-vegf-inhibitor-pazopanib-and-mek-inhibitor-trametinib-in-advanced-soft-tissue-sarcoma
#9
Vivek Subbiah, Christian Meyer, Ralph Zinner, Funda Meric-Bernstam, Marianna L Zahurak, Ashley O'Connor, Jason Roszik, Kenna Shaw, Joseph A Ludwig, Razelle Kurzrock, Nilofer A Azad
Purpose: Pazopanib, a multi-receptor tyrosine kinase inhibitor targeting primarily vascular endothelial growth factor receptors 1-3 (VEGFRs1-3), is approved for advanced soft tissue sarcoma and renal cell cancer. Downstream of VEGFR, trametinib is an FDA-approved MEK inhibitor used for melanoma. We hypothesized that vertical pathway inhibition using a trametinib would synergize with pazopanib in advanced soft tissue sarcoma (STS). <p>Experimental Design: In an open-label, multicenter, investigator-initiated NCCN-sponsored trial, patients with metastatic or advanced STS received pazopanib 800 mg and 2 mg of trametinib continuously for 28-day cycles...
April 4, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28350009/activation-of-erk1-2-causes-pazopanib-resistance-via-downregulation-of-dusp6-in-synovial-sarcoma-cells
#10
Nobuhiko Yokoyama, Tomoya Matsunobu, Yoshihiro Matsumoto, Jun-Ichi Fukushi, Makoto Endo, Mihoko Hatano, Akira Nabeshima, Suguru Fukushima, Seiji Okada, Yukihide Iwamoto
Synovial sarcoma (SS) is a rare high-grade malignant mesenchymal tumour with a relatively poor prognosis despite intensive multimodal therapy. Although pazopanib, a multi-kinase inhibitor, is often used for advanced SS, most cases eventually become resistant to pazopanib. In the present study, we investigated the mechanisms of acquired pazopanib resistance in SS. To examine acquired pazopanib resistance, two SS cell lines, SYO-1 and HS-SY-II, were isolated after multiple selection steps with increasing concentrations of pazopanib...
March 28, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28344857/metastatic-braf-k601e-mutated-melanoma-reaches-complete-response-to-mek-inhibitor-trametinib-administered-for-over-36%C3%A2-months
#11
Riccardo Marconcini, Luca Galli, Andrea Antonuzzo, Simona Bursi, Claudia Roncella, Gabriella Fontanini, Elisa Sensi, Alfredo Falcone
BACKGROUND: The BRAF K601E mutation occurs in 5% of patients with melanoma, and is the third most common type of BRAF mutation. However, treatment with BRAF and mitogen-activated extracellular signal-regulated kinase (MEK) inhibitors is only approved in patients with BRAF V600-positive melanoma, and patients with K601E-mutated melanoma do not have access to such drugs. CASE PRESENTATION: A female patient was diagnosed with high tumor burden metastatic melanoma harboring the BRAF K601E mutation...
2017: Experimental Hematology & Oncology
https://www.readbyqxmd.com/read/28320730/prediction-of-the-transporter-mediated-drug-drug-interaction-potential-of-dabrafenib-and-its-major-circulating-metabolites
#12
Harma Ellens, Marta Johnson, Sarah K Lawrence, Cory A 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 MEK inhibitor trametinib. This article presents the dabrafenib transporter-mediated drug-drug interaction 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 Pgp, BCRP, OATP1B1, OATP1B3, OCT2, OAT1 and OAT3...
March 20, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28303522/nanotechnology-for-the-treatment-of-melanoma-skin-cancer
#13
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/28301591/in-vivo-and-ex-vivo-cetuximab-sensitivity-assay-using-three-dimensional-primary-culture-system-to-stratify-kras-mutant-colorectal-cancer
#14
Takahiro Tashiro, Hiroaki Okuyama, Hiroko Endo, Kenji Kawada, Yasuko Ashida, Masayuki Ohue, Yoshiharu Sakai, Masahiro Inoue
In clinic, cetuximab, an anti-EGFR antibody, improves treatment outcomes in colorectal cancer (CRC). KRAS-mutant CRC is generally resistant to cetuximab, although difference of the sensitivity among KRAS-mutants has not been studied in detail. We previously developed the cancer tissue-originated spheroid (CTOS) method, a primary culture method for cancer cells. We applied CTOS method to investigate whether ex vivo cetuximab sensitivity assays reflect the difference in sensitivity in the xenografts. Firstly, in vivo cetuximab treatment was performed with xenografts derived from 10 CTOS lines (3 KRAS-wildtype and 7 KRAS mutants)...
2017: PloS One
https://www.readbyqxmd.com/read/28281325/b-raf-mutations-are-associated-with-increased-iron-regulatory-protein-2-expression-in-colorectal-tumourigenesis
#15
Richard D Horniblow, Matthew Bedford, Robert Hollingworth, Sarah Evans, Emily Sutton, Neeraj Lal, Andrew Beggs, Tariq H Iqbal, Chris Tselepis
A role for iron in carcinogenesis is supported by evidence that iron metabolism proteins are modulated in cancer progression. To date however, the expression of IRP2 (Iron Regulatory Protein-2), which is known to regulate several iron metabolism proteins, has not been assessed in colorectal cancer. Expression of IRP2 was assessed by qRT-PCR and immunohistochemistry in human colorectal cancer tissue. By interrogating The Cancer Genome Atlas (TCGA) database, expression of IRP2 and transferrin receptor-1 (TfR1) was assessed relative to common mutations that are known to occur in cancer...
March 9, 2017: Cancer Science
https://www.readbyqxmd.com/read/28278423/digoxin-plus-trametinib-therapy-achieves-disease-control-in-braf-wild-type-metastatic-melanoma-patients
#16
Arthur E Frankel, Ugur Eskiocak, Jennifer G Gill, Stacy Yuan, Vijayashree Ramesh, Thomas W Froehlich, Chul Ahn, Sean J Morrison
This is the first prospective study of a combination therapy involving a cardenolide and a MEK inhibitor for metastatic melanoma. Whereas BRAF mutant melanomas can exhibit profound responses to treatment with BRAF and MEK inhibitors, there are fewer options for BRAF wild-type melanomas. In preclinical studies, we discovered that cardenolides synergize with MEK inhibitor to promote the regression of patient-derived xenografts irrespective of BRAF mutation status. We therefore conducted a phase 1B study of digoxin 0...
April 2017: Neoplasia: An International Journal for Oncology Research
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
#17
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
https://www.readbyqxmd.com/read/28253523/mek-inhibition-appears-to-improve-symptom-control-in-primary-nras-driven-cns-melanoma-in-children
#18
Veronica A Kinsler, Patricia O'Hare, Thomas Jacques, Darren Hargrave, Olga Slater
BACKGROUND: Primary melanoma of the CNS in children is extremely rare, and usually linked to congenital melanocytic naevus syndrome, caused by mosaicism for oncogenic NRAS mutations. Outcome is fatal in all cases. Data from murine and in vitro studies suggest that MEK inhibition is a possible therapeutic option. METHODS: Four children with NRAS-mutated CNS melanoma were treated with Trametinib on a compassionate basis. RESULTS: All four had an improvement in symptoms and objectively in signs...
April 11, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/28252479/dabrafenib-plus-trametinib-rechallenge-in-four-melanoma-patients-who-previously-progressed-on-this-combination
#19
Aljosja Rogiers, Pascal Wolter, Oliver Bechter
In unresectable or metastatic melanoma with a BRAF V600 mutation, combined BRAF/MEK targeted therapy improves clinical outcomes. Yet, disease progression because of acquired resistance occurs in the majority of patients. There is emerging evidence that resistance to BRAF-inhibitor-based targeted therapy can be reversible in some cases. We retrospectively analyzed four patients with BRAF-mutant stage IV cutaneous melanoma who were treated with dabrafenib plus trametinib and rechallenged with the same combination after previously experiencing progression...
April 2017: Melanoma Research
https://www.readbyqxmd.com/read/28242136/braf-signaling-pathway-inhibition-podocyte-injury-and-nephrotic-syndrome
#20
Luca Perico, Mario Mandalà, Arrigo Schieppati, Camillo Carrara, Paola Rizzo, Sara Conti, Lorena Longaretti, Ariela Benigni, Giuseppe Remuzzi
Dabrafenib and trametinib, BRAF and MEK inhibitors, respectively, are effective targeted metastatic melanoma therapies, but little is known about their nephrotoxicity. Although tubulointerstitial injury has been the most widely reported renal side effect of targeted melanoma therapy, nephrotic syndrome has not been reported before. We report on a patient with metastatic melanoma who developed nephrotic syndrome during dabrafenib and trametinib treatment. Kidney biopsy showed diffuse loss of podocyte cytoarchitecture, extensive foot-process effacement, and glomerular endothelial injury...
February 24, 2017: American Journal of Kidney Diseases: the Official Journal of the National Kidney Foundation
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