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https://www.readbyqxmd.com/read/28194436/real-time-genomic-profiling-of-histiocytoses-identifies-early-kinase-domain-braf-alterations-while-improving-treatment-outcomes
#1
Lynn H Lee, Anjelika Gasilina, Jayeeta Roychoudhury, Jason Clark, Francis X McCormack, Joseph Pressey, Michael S Grimley, Robert Lorsbach, Siraj Ali, Mark Bailey, Philip Stephens, Jeffrey S Ross, Vincent A Miller, Nicolas N Nassar, Ashish R Kumar
Many patients with histiocytic disorders such as Langerhans cell histiocytosis (LCH) or Erdheim-Chester disease (ECD) have treatment-refractory disease or suffer recurrences. Recent findings of gene mutations in histiocytoses have generated options for targeted therapies. We sought to determine the utility of prospective sequencing of select genes to further characterize mutations and identify targeted therapies for patients with histiocytoses. Biopsies of 72 patients with a variety of histiocytoses underwent comprehensive genomic profiling with targeted DNA and RNA sequencing...
February 9, 2017: JCI Insight
https://www.readbyqxmd.com/read/28182109/acute-truncal-lymphedema-secondary-to-axillary-metastatic-melanoma-presenting-like-cellulitis
#2
Shelley J E Hwang, Benjamin Y Kong, Shaun Chou, Deepal Wakade, Matteo S Carlino, Pablo Fernandez-Penas
There are reported cases of diphencyprone used in treating cutaneous metastases of melanoma. Here, we report a patient with previous primary melanoma on his left back treated with surgical excision and lymphadenectomy, followed by radiotherapy for the recurrent tumor on the primary site. Despite radiotherapy and treatment with dabrafenib and trametinib, in-transit metastases have developed and topical diphencyprone was applied to these metastases. Six weeks later, the patient developed fever and a spreading erythematous tender indurated plaque covering the left side of the body including axillae, back, and flank, clinically suggestive of cellulitis...
2017: Case Reports in Medicine
https://www.readbyqxmd.com/read/28178529/atxn1l-cic-and-ets-transcription-factors-modulate-sensitivity-to-mapk-pathway-inhibition
#3
Belinda Wang, Elsa Beyer Krall, Andrew James Aguirre, Miju Kim, Hans Ragnar Widlund, Mihir Bhavik Doshi, Ewa Sicinska, Rita Sulahian, Amy Goodale, Glenn Spencer Cowley, Federica Piccioni, John Gerard Doench, David Edward Root, William Chun Hahn
Intrinsic resistance and RTK-RAS-MAPK pathway reactivation has limited the effectiveness of MEK and RAF inhibitors (MAPKi) in RAS- and RAF-mutant cancers. To identify genes that modulate sensitivity to MAPKi, we performed genome-scale CRISPR-Cas9 loss-of-function screens in two KRAS mutant pancreatic cancer cell lines treated with the MEK1/2 inhibitor trametinib. Loss of CIC, a transcriptional repressor of ETV1, ETV4, and ETV5, promoted survival in the setting of MAPKi in cancer cells derived from several lineages...
February 7, 2017: Cell Reports
https://www.readbyqxmd.com/read/28178388/molecular-targeting-therapies-against-quantitative-abnormalities-in-gene-expression-with-malignant-tumors
#4
REVIEW
Toshiyuki Sakai, Yoshihiro Sowa
Genetic mutations in exons of oncogenes and tumor-suppressor genes causing qualitative abnormalities result in activation of the oncogenes and inactivation of the tumor-suppressor genes, thereby causing cancer. In contrast, we have previously demonstrated that decreases in the RB promoter activity by genetic or epigenetic abnormalities can also cause carcinogenesis. In addition, activation and inactivation of a variety of oncogenes and tumor-suppressor genes finally cause quantitative abnormalities in gene expression...
February 8, 2017: Cancer Science
https://www.readbyqxmd.com/read/28157711/the-repurposed-anthelmintic-mebendazole-in-combination-with-trametinib-suppresses-refractory-nrasq61k-melanoma
#5
Cynthia M Simbulan-Rosenthal, Sivanesan Dakshanamurthy, Anirudh Gaur, You-Shin Chen, Hong-Bin Fang, Maryam Abdussamad, Hengbo Zhou, John Zapas, Valerie Calvert, Emanuel F Petricoin, Michael B Atkins, Stephen W Byers, Dean S Rosenthal
Structure-based drug repositioning in addition to random chemical screening is now a viable route to rapid drug development. Proteochemometric computational methods coupled with kinase assays showed that mebendazole (MBZ) binds and inhibits kinases important in cancer, especially both BRAFWT and BRAFV600E. We find that MBZ synergizes with the MEK inhibitor trametinib to inhibit growth of BRAFWT-NRASQ61K melanoma cells in culture and in xenografts, and markedly decreased MEK and ERK phosphorylation. Reverse Phase Protein Array (RPPA) and immunoblot analyses show that both trametinib and MBZ inhibit the MAPK pathway, and cluster analysis revealed a protein cluster showing strong MBZ+trametinib - inhibited phosphorylation of MEK and ERK within 10 minutes, and its direct and indirect downstream targets related to stress response and translation, including ElK1 and RSKs within 30 minutes...
February 2, 2017: Oncotarget
https://www.readbyqxmd.com/read/28151720/biomarker-and-tumor-responses-of-oral-cavity-squamous-cell-carcinoma-to-trametinib-a-phase-ii-neoadjuvant-window-of-opportunity-clinical-trial
#6
Ravindra Uppaluri, Ashley E Winkler, Tianxiang Lin, Jonathan H Law, Bruce H Haughey, Brian Nussenbaum, Randal C Paniello, Jason T Rich, Jason A Diaz, Loren S Michel, Tanya Wildes, Gavin P Dunn, Paul Zolkind, Dorina Kallogjeri, Jay F Piccirillo, Farrokh Dehdashti, Barry A Siegel, Rebecca D Chernock, James S Lewis, Douglas R Adkins
PURPOSE: Ras/MEK/ERK pathway activation is common in oral cavity squamous cell carcinoma (OCSCC). We performed a neoadjuvant (pre-operative) trial to determine biomarker and tumor response of OCSCC to MEK inhibition with trametinib. EXPERIMENTAL DESIGN: Patients with Stage II-IV OCSCC received trametinib (2 mg/day, minimum 7 days) prior to surgery. Primary tumor specimens were obtained before and after trametinib to evaluate immunohistochemistry staining for p-ERK½ and CD44, the primary endpoint...
November 9, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28146421/the-hdac-inhibitor-ar42-interacts-with-pazopanib-to-kill-trametinib-dabrafenib-resistant-melanoma-cells-in-vitro-and-in-vivo
#7
Laurence Booth, Jane L Roberts, Cindy Sander, John Lee, John M Kirkwood, Andrew Poklepovic, Paul Dent
Studies focused on the killing of activated B-RAF melanoma cells by the histone deacetylase (HDAC) inhibitor AR42. Compared to other tumor cell lines, PDX melanoma isolates were significantly more sensitive to AR42-induced killing. AR42 and the multi-kinase inhibitor pazopanib interacted to activate: an eIF2α-Beclin1 pathway causing autophagosome formation; an eIF2α-DR4/DR5/CD95 pathway; and an eIF2α-dependent reduction in the expression of c-FLIP-s, MCL-1 and BCL-XL. AR42 did not alter basal chaperone activity but increased the ability of pazopanib to inhibit HSP90, HSP70 and GRP78...
January 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/28138035/co-targeting-hgf-cmet-signaling-with-mek-inhibitors-in-metastatic-uveal-melanoma
#8
Hanyin Cheng, Vivian Chua, Connie Liao, Timothy J Purwin, Mizue Terai, Ken Kageyama, Michael A Davies, Takami Sato, Andrew E Aplin
Metastatic uveal melanoma (UM) patients usually die within one year of diagnosis, emphasizing an urgent need to develop new treatment strategies. The liver is the most common site of metastasis. Mitogen-activated protein kinase kinase (MEK) inhibitors improve survival in V600 BRAF-mutated cutaneous melanoma patients but have limited efficacy in UM patients. Our previous work showed that HGF signaling elicits resistance to MEK inhibitors in metastatic UM. In this study, we demonstrate that expression of two BH3-only family proteins, Bim-EL and BMF, contributes to HGF-mediated resistance to MEK inhibitors...
January 30, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28132803/combined-blockade-of-tim-3-and-mek-inhibitor-enhances-the-efficacy-against-melanoma
#9
Yang Liu, Pengcheng Cai, Ning Wang, Qianwen Zhang, Fenghua Chen, Liang Shi, Yang Zhang, Lin Wang, Lihua Hu
Insights into the role of the mitogen-activated protein kinase (MAPK) pathway and immune checkpoints have led combined targeted therapy and immunotherapy to be a promising regimen. Trametinib, as a mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor, has demonstrated effectiveness in patients with advanced melanoma. T cell immunoglobulin- and mucin-domain-containing molecule-3 (Tim-3), an immune checkpoint molecule, participates in multiple negative regulation of antitumor immunity. We for the first time to our knowledge reported the combination of trametinib and anti-Tim-3 monoclonal antibody (mAb) in treating B16-F10 melanoma mice...
January 26, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28129642/the-purpose-of-repurposing
#10
EDITORIAL
James E Barrett, Felix J Kim
News on: The repurposed anthelmintic mebendazole in combination with trametinib suppresses refractory NRASQ61K melanoma by Dean Rosenthal, et al. Oncotarget, 2016, in press.
January 24, 2017: Oncotarget
https://www.readbyqxmd.com/read/28110826/congenital-melanocytic-nevus-syndrome-a-case-series
#11
A Recio, A I Sánchez-Moya, V Félix, Y Campos
Congenital melanocytic nevus syndrome (CMNS) is the result of an abnormal proliferation of melanocytes in the skin and central nervous system caused by progenitor-cell mutations during embryonic development. Mutations in the NRAS gene have been detected in many of these cells. We present 5 cases of giant congenital melanocytic nevus, 3 of them associated with CMNS; NRAS gene mutation was studied in these 3 patients. Until a few years ago, surgery was the treatment of choice, but the results have proved unsatisfactory because aggressive interventions do not improve cosmetic appearance and only minimally reduce the risk of malignant change...
January 19, 2017: Actas Dermo-sifiliográficas
https://www.readbyqxmd.com/read/28108460/enhancer-remodeling-during-adaptive-bypass-to-mek-inhibition-is-attenuated-by-pharmacological-targeting-of-the-p-tefb-complex
#12
Jon S Zawistowski, Samantha M Bevill, Daniel R Goulet, Timothy J Stuhlmiller, Adriana S Beltran, Jose F Olivares-Quintero, Darshan Singh, Noah Sciaky, Joel S Parker, Naim U Rashid, Xin Chen, James S Duncan, Martin C Whittle, Steven P Angus, Sara Hanna Velarde, Brian T Golitz, Xiaping He, Charlene Santos, David B Darr, Kristalyn Gallagher, Lee M Graves, Charles M Perou, Lisa A Carey, H Shelton Earp, Gary L Johnson
Targeting the dysregulated BRaf-MEK-ERK pathway in cancer has increasingly emerged in clinical trial design. Despite clinical responses in specific cancers using inhibitors targeting BRaf and MEK, resistance develops often involving non-genomic adaptive bypass mechanisms. Inhibition of MEK1/2 by trametinib in triple negative breast cancer (TNBC) patients induced dramatic transcriptional responses, including upregulation of receptor tyrosine kinases (RTKs) comparing tumor samples before and after one week of treatment...
January 20, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28106277/tumor-targeting-salmonella-typhimurium-a1-r-sensitizes-melanoma-with-a-braf-v600e-mutation-to-vemurafenib-in-a-patient-derived-orthotopic-xenograft-pdox-nude-mouse-model
#13
Kei Kawaguchi, Kentaro Igarashi, Takashi Murakami, Ming Zhao, Yong Zhang, Bartosz Chmielowski, Tasuku Kiyuna, Scott D Nelson, Tara A Russell, Sarah M Dry, Yunfeng Li, Michiaki Unno, Fritz C Eilber, Robert M Hoffman
Previously, 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 patient-derived orthotopic xenograft (PDOX) model. Tumor sizes were measured with calipers twice a week. On day 14 from initiation of treatment, trametinib (TRA), an MEK inhibitor, caused tumor regression. In contrast, another MEK inhibitor, cobimetinib (COB) could slow but not arrest growth or cause regression of the melanoma. First-line therapy temozolomide (TEM) could slow but not arrest tumor growth or cause regression...
January 20, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28092667/oncogenic-braf-fusions-in-mucosal-melanomas-activate-the-mapk-pathway-and-are-sensitive-to-mek-pi3k-inhibition-or-mek-cdk4-6-inhibition
#14
H S Kim, M Jung, H N Kang, H Kim, C-W Park, S-M Kim, S J Shin, S H Kim, S G Kim, E K Kim, M R Yun, Z Zheng, K Y Chung, J Greenbowe, S M Ali, T-M Kim, B C Cho
Despite remarkable progress in cutaneous melanoma genomic profiling, the mutational landscape of primary mucosal melanomas (PMM) remains unclear. Forty-six PMMs underwent targeted exome sequencing of 111 cancer-associated genes. Seventy-six somatic nonsynonymous mutations in 42 genes were observed, and recurrent mutations were noted on eight genes, including TP53 (13%), NRAS (13%), SNX31 (9%), NF1 (9%), KIT (7%) and APC (7%). Mitogen-activated protein kinase (MAPK; 37%), cell cycle (20%) and phosphatidylinositol 3-kinase (PI3K)-mTOR (15%) pathways were frequently mutated...
January 16, 2017: Oncogene
https://www.readbyqxmd.com/read/28090569/mitogen-activated-protein-kinase-kinase-activity-maintains-acinar-to-ductal-metaplasia-and-is-required-for-organ-regeneration-in-pancreatitis
#15
Christopher J Halbrook, Hui-Ju Wen, Jeanine M Ruggeri, Kenneth K Takeuchi, Yaqing Zhang, Marina Pasca di Magliano, Howard C Crawford
BACKGROUND & AIMS: Mitogen-activated protein kinase (MAPK) signaling in the exocrine pancreas has been extensively studied in the context of pancreatic cancer, where its potential as a therapeutic target is limited by acquired drug resistance. However, its role in pancreatitis is less understood. We investigated the role of mitogen-activated protein kinase kinase (MEK)-initiated MAPK signaling in pancreatitis to determine the potential for MEK inhibition in treating pancreatitis patients...
January 2017: Cellular and Molecular Gastroenterology and Hepatology
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
#16
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
#17
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/28067893/vemurafenib-and-trametinib-reduce-expression-of-ctgf-and-il-8-in-v600e-braf-melanoma-cells
#18
Mariusz L Hartman, Michal Rozanski, Marta Osrodek, Izabela Zalesna, Malgorzata Czyz
Clinical evidence has revealed that while RAS/RAF/MEK/ERK pathway is a crucial component of melanomagenesis, other signaling pathways can also contribute to the malignant growth and development of resistance to targeted therapies. We explored the response of (V600E)BRAF melanoma cells derived from surgical specimens and grown in stem cell medium to vemurafenib and trametinib, drugs targeting the activity of (V600E)BRAF and MEK1/2, respectively. Cell growth and apoptosis were monitored by real-time imaging system, immunophenotype and cell cycle by flow cytometry, gene expression by quantitative real-time PCR, immunoblotting and enzyme-linked immunosorbent assay...
January 9, 2017: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://www.readbyqxmd.com/read/28062673/dabrafenib-effective-in-pediatric-glioma
#19
(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
#20
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...
February 2017: BioDrugs: Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy
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