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https://www.readbyqxmd.com/read/28303522/nanotechnology-for-the-treatment-of-melanoma-skin-cancer
#1
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
#2
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
#3
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
#4
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...
March 6, 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
#5
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...
March 3, 2017: Lancet Oncology
https://www.readbyqxmd.com/read/28253523/mek-inhibition-appears-to-improve-symptom-control-in-primary-nras-driven-cns-melanoma-in-children
#6
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...
March 2, 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
#7
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
#8
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
https://www.readbyqxmd.com/read/28224120/oncolytic-virotherapy-including-rigvir-and-standard-therapies-in-malignant-melanoma
#9
REVIEW
Hani M Babiker, Irbaz Bin Riaz, Muhammad Husnain, Mitesh J Borad
The treatment of metastatic melanoma has evolved from an era where interferon and chemotherapy were the mainstay of treatments to an era where immunotherapy has become the frontline. Ipilimumab (IgG1 CTLA-4 inhibitor), nivolumab (IgG4 PD-1 inhibitor), pembrolizumab (IgG4 PD-1 inhibitor) and nivolumab combined with ipilimumab have become first-line therapies in patients with metastatic melanoma. In addition, the high prevalence of BRAF mutations in melanoma has led to the discovery and approval of targeted molecules, such as vemurafenib (BRAF kinase inhibitor) and trametinib (MEK inhibitor), as they yielded improved responses and survival in malignant melanoma patients...
2017: Oncolytic Virotherapy
https://www.readbyqxmd.com/read/28194436/real-time-genomic-profiling-of-histiocytoses-identifies-early-kinase-domain-braf-alterations-while-improving-treatment-outcomes
#10
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
#11
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
#12
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
#13
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
#14
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
#15
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
#16
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
#17
Hanyin Cheng, Vivian Chua, Connie Liao, Timothy J Purwin, Mizue Terai, Ken Kageyama, Michael A Davies, Takami Sato, Andrew E Aplin
Patients with metastatic uveal melanoma usually die within 1 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 patients with uveal melanoma. Our previous work showed that hepatocyte growth factor (HGF) signaling elicits resistance to MEK inhibitors in metastatic uveal melanoma...
March 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28132803/combined-blockade-of-tim-3-and-mek-inhibitor-enhances-the-efficacy-against-melanoma
#18
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
#19
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
#20
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
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