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https://www.readbyqxmd.com/read/28062115/genotype-matched-treatment-for-patients-with-advanced-type-i-epithelial-ovarian-cancer-eoc
#1
A Spreafico, A M Oza, B A Clarke, H J Mackay, P Shaw, M Butler, N C Dhani, S Lheureux, M K Wilson, S Welch, T Zhang, C Yu, T Stockley, L L Siu, S Kamel-Reid, P L Bedard
BACKGROUND: Genomic alterations that activate the MAPK signaling pathway frequently occur in Type I Epithelial Ovarian Cancers (EOCs). We evaluated therapeutic response outcomes in patients with type I EOC treated with genotype-matched therapy on clinical trials enrolled in a prospective molecular profiling program. MATERIAL AND METHODS: Formalin fixed paraffin embedded tumor tissues were prospectively screened for genomic alterations using MALDI-ToF mass-spectrometry platform or targeted sequencing using the Illumina MiSeq TruSeq Amplicon Cancer Panel...
January 3, 2017: Gynecologic Oncology
https://www.readbyqxmd.com/read/28057557/anesthetics-inhibit-extracellular-signal-regulated-kinase1-2-phosphorylation-via-nmda-receptor-phospholipase-c-and-protein-kinase-c-in-mouse-hippocampal-slices
#2
Gao Haiying, Han Mingjie, Zhang Lingyu, Wang Qingxiang, Wang Haisong, Zhang Bingxi
BACKGROUND: Extracellular signal-regulated kinase 1/2 (ERK1/2) has been implicated in learning and memory; however, whether intravenous anesthetics modulate ERK1/2 remains unknown. The aim of this study was to examine the effect of several intravenous anesthetics on the phosphorylation of ERK1/2 in the hippocampus of adult mice. METHODS: Western blotting was used to examine cellular levels of phosphorylated and unphosphorylated ERK1/2 in mouse hippocampus slices, which were incubated with or without anesthetics including propofol, etomidate, ketamine and midazolam, a protein kinase C (PKC) activator or inhibitor, or phospholipase C (PLC) activator or inhibitor...
January 3, 2017: Neurochemistry International
https://www.readbyqxmd.com/read/27991907/immunomodulating-property-of-mapk-inhibitors-from-translational-knowledge-to-clinical-implementation
#3
Mario Mandalà, Francesco De Logu, Barbara Merelli, Romina Nassini, Daniela Massi
Treatment of metastatic melanoma was radically changed by the introduction of inhibitors of BRAF, an oncogene mutated in 40-50% of patients. Another area of advancement was the use of immunotherapy, and specifically, immune checkpoint inhibitors. There is compelling evidence that oncogenic BRAF, in addition to driving melanoma proliferation, differentiation and survival, induces T-cell suppression directly through the secretion of inhibitory cytokines or through membrane expression of co-inhibitory molecules such as the PD-1 ligands PD-L1 or PD-L2...
December 19, 2016: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://www.readbyqxmd.com/read/27988307/interleukin-6-and-neuregulin-1-as-regulators-of-utrophin-expression-via-the-activation-of-nrg-1-erbb-signaling-pathway-in-mdx-cells
#4
Nevenka Juretić, Josefina Díaz, Felipe Romero, Gustavo González, Enrique Jaimovich, Nora Riveros
Duchenne muscular dystrophy (DMD) is a neuromuscular disease originated by mutations in the dystrophin gene. A promising therapeutic approach deals with functional substitution of dystrophin by utrophin, a structural homolog that might be able to compensate dystrophin absence in DMD muscle fibers. It has been described that both interleukin-6 (IL-6) and neuregulin-1 (NRG-1; Heregulin-HRG) induce utrophin expression in skeletal muscle. We investigated a possible functional link among IL-6, NRG-1 and utrophin, in normal (C57) and dystrophic (mdx) skeletal muscle cells...
December 15, 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27867002/trametinib-plus-4-methylumbelliferone-exhibits-antitumor-effects-by-erk-blockade-and-cd44-downregulation-and-affects-pd1-and-pd-l1-in-malignant-pleural-mesothelioma
#5
Hiroyuki Cho, Seiji Matsumoto, Yoshiko Fujita, Ayumi Kuroda, Toshi Menju, Makoto Sonobe, Nobuyuki Kondo, Ikuko Torii, Takashi Nakano, Primo N Lara, David R Gandara, Hiroshi Date, Seiki Hasegawa
INTRODUCTION: Malignant pleural mesothelioma (MPM) is a highly aggressive malignancy in which the mitogen-activated protein kinase (MAPK) pathway plays a critical role in the regulation of tumorigenesis. Hyaluronan (HA) is a major component of the extracellular matrix, and elevated HA levels, with a concurrent increase in malignant properties, are associated with MPM. METHODS: We evaluated the effects of trametinib, a MAPK kinase enzyme (MEK) inhibitor, and 4-methylumbelliferone (4-MU), an HA synthesis inhibitor, alone and in combination on MPM cells in vitro and in vivo...
November 17, 2016: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/27846317/ras-mitogen-activated-protein-kinase-signal-is-required-for-enhanced-pd-l1-expression-in-human-lung-cancers
#6
Hidetoshi Sumimoto, Atsushi Takano, Koji Teramoto, Yataro Daigo
Ectopic programmed cell death ligand 1 (PD-L1) expression in non-small cell lung cancers (NSCLCs) is related to immune evasion by cancer, and it is a molecular target of immune checkpoint therapies. Although some altered signals in NSCLCs are responsible for ectopic PD-L1 expression, the precise mechanisms remain obscure. Because we found a higher frequency of EGFR/KRAS mutations in NSCLC cell lines with high PD-L1 expression (p < 0.001), we evaluated the relationships between downstream signals and PD-L1 expression, particularly in three KRAS-mutant adenocarcinoma cell lines...
2016: PloS One
https://www.readbyqxmd.com/read/27846054/sequencing-treatment-in-brafv600-mutant-melanoma-anti-pd-1-before-and-after-braf-inhibition
#7
Douglas B Johnson, Eirini Pectasides, Emily Feld, Fei Ye, Shilin Zhao, Romany Johnpulle, Ryan Merritt, David F McDermott, Igor Puzanov, Donald Lawrence, Jeffrey A Sosman, Elizabeth Buchbinder, Ryan J Sullivan
Novel agents targeting immune checkpoint molecules or mutated BRAF are active therapeutic options for patients with BRAF-mutant melanoma. However, the most effective first-line treatment and the optimal sequencing of these agents have not been well characterized. To explore this, we retrospectively assessed 114 patients from 4 centers with advanced, BRAF-mutant melanoma who received anti-programmed cell death-1 (PD-1)/PD-L1 antibodies. We evaluated clinical outcomes, including objective response rate (ORR), overall survival (OS), and progression-free survival (PFS) to initial and subsequent therapies in patients that received anti-PD-1 first (n=56) versus those that received BRAF±MEK inhibitors (BRAFi) first (n=58)...
January 2017: Journal of Immunotherapy
https://www.readbyqxmd.com/read/27833160/photothermal-therapy-improves-the-efficacy-of-a-mek-inhibitor-in-neurofibromatosis-type-1-associated-malignant-peripheral-nerve-sheath-tumors
#8
Elizabeth E Sweeney, Rachel A Burga, Chaoyang Li, Yuan Zhu, Rohan Fernandes
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive tumors with low survival rates and the leading cause of death in neurofibromatosis type 1 (NF1) patients under 40 years old. Surgical resection is the standard of care for MPNSTs, but is often incomplete and can generate loss of function, necessitating the development of novel treatment methods for this patient population. Here, we describe a novel combination therapy comprising MEK inhibition and nanoparticle-based photothermal therapy (PTT) for MPNSTs...
November 11, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27787543/systemic-therapy-for-previously-untreated-advanced-braf-mutated-melanoma-a-systematic-review-and-network-meta-analysis-of-randomized-clinical-trials
#9
Tahira Devji, Oren Levine, Binod Neupane, Joseph Beyene, Feng Xie
Importance: Multiple effective first-line systemic treatment options are available for patients with advanced BRAF-mutated melanoma. A lack of head-to-head randomized clinical trials (RCTs) comparing targeted and immunotherapies leaves uncertainty regarding optimal first-line treatment. Objective: To estimate the relative efficacy and safety of systemic therapies for advanced, treatment-naive, BRAF-mutated melanoma. Data Sources: We searched MEDLINE, Embase, and the Cochrane Central Registry of Controlled Trials for phase 2 or 3 RCTs published up until April 29, 2016...
October 27, 2016: JAMA Oncology
https://www.readbyqxmd.com/read/27710977/the-systemic-management-of-advanced-melanoma-in-2016
#10
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
https://www.readbyqxmd.com/read/27693888/a-phase-i-pharmacokinetic-and-pharmacodynamic-study-of-the-oral-mitogen-activated-protein-kinase-kinase-mek-inhibitor-wx-554-in-patients-with-advanced-solid-tumours
#11
David Jamieson, Melanie J Griffin, Julieann Sludden, Yvette Drew, Nicola Cresti, Karen Swales, Mark Merriman, Rodger Allen, Paul Bevan, Markus Buerkle, Carola Mala, Vicky Coyle, Lisa Rodgers, Emma Dean, Alastair Greystoke, Udai Banerji, Richard H Wilson, T R Jeffery Evans, Alan Anthoney, Malcolm Ranson, Alan V Boddy, Ruth Plummer
PURPOSE: We performed a multi-centre phase I study to assess the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of the orally available small molecule mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor, WX-554, and to determine the optimal biological dose for subsequent trials. EXPERIMENTAL DESIGN: Patients with treatment-refractory, advanced solid tumours, with adequate performance status and organ function were recruited to a dose-escalation study in a standard 3 + 3 design...
September 28, 2016: European Journal of Cancer
https://www.readbyqxmd.com/read/27637745/clinical-outcomes-of-melanoma-brain-metastases-treated-with-stereotactic-radiosurgery-and-anti-pd-1-therapy-anti-ctla-4-therapy-braf-mek-inhibitors-braf-inhibitor-or-conventional-chemotherapy
#12
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...
December 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/27628745/recent-progress-in-mutation-driven-therapy-immunotherapy-and-combination-therapy-for-the-treatment-of-melanoma
#13
Hazem Ihsan Assi, Rita Assi
With increases in our understanding of the human genome and immune system, the treatment armamentarium for melanoma has benefitted from the development and approval of BRAF inhibitors, MEK inhibitors, immune checkpoint modulators via cytotoxic T-lymphocyte antigen-4 blockade, and PD-1 and PD-L1 inhibitors. These advances, however, have raised questions about combination therapy, the optimal sequential use of these agents, the limited assessment of response using traditional metrics, and the optimal selection of the population to be treated...
July 19, 2016: Current Cancer Drug Targets
https://www.readbyqxmd.com/read/27622011/combined-treatment-with-dabrafenib-and-trametinib-with-immune-stimulating-antibodies-for-braf-mutant-melanoma
#14
Blanca Homet Moreno, Stephen Mok, Begonya Comin-Anduix, Siwen Hu-Lieskovan, Antoni Ribas
The combination of targeted therapy with BRAF and MEK inhibitors has become the standard of care in patients with BRAF (V600E) mutant melanoma, but responses are not durable. In addition, the impressive clinical benefits with anti-PD-1 and anti-PD-L1 antibodies (Ab) in patients with heavily pretreated metastatic melanoma and the synergistic effect of dabrafenib, trametinib and anti-PD-1 compared with single therapy alone groups support the idea that combining dabrafenib, trametinib and immunotherapy based on PD-1 blockade could be an interesting approach in the treatment of metastatic melanoma...
July 2016: Oncoimmunology
https://www.readbyqxmd.com/read/27595232/the-mucin-muc1-modulates-the-tumor-immunological-microenvironment-through-engagement-of-the-lectin-siglec-9
#15
Richard Beatson, Virginia Tajadura-Ortega, Daniela Achkova, Gianfranco Picco, Theodora-Dorita Tsourouktsoglou, Sandra Klausing, Matthew Hillier, John Maher, Thomas Noll, Paul R Crocker, Joyce Taylor-Papadimitriou, Joy M Burchell
Siglec-9 is a sialic-acid-binding lectin expressed predominantly on myeloid cells. Aberrant glycosylation occurs in essentially all types of cancers and results in increased sialylation. Thus, when the mucin MUC1 is expressed on cancer cells, it is decorated by multiple short, sialylated O-linked glycans (MUC1-ST). Here we found that this cancer-specific MUC1 glycoform, through engagement of Siglec-9, 'educated' myeloid cells to release factors associated with determination of the tumor microenvironment and disease progression...
November 2016: Nature Immunology
https://www.readbyqxmd.com/read/27583191/indomethacin-induces-increase-in-gastric-epithelial-tight-junction-permeability-via-redistribution-of-occludin-and-activation-of-p38-mapk-in-mkn-28-cells
#16
Meghali Thakre-Nighot, Anthony T Blikslager
Tight Junctions (TJ) create a paracellular barrier that is compromised when nonsteriodal anti-inflammatory drugs (NSAIDs) injure the gastric epithelium, leading to increased permeability. However, the mechanism of NSAID-induced gastric injury is unclear. Here, we examined the effect of indomethacin on barrier function and TJ in gastric MKN-28 cells. In concentration response studies, 500 µm indomethacin induced a significant decrease in transepithelial resistance (TER; 380 vs. 220 Ω·cm(2) for control and indomethacin-treated cells respectively, p < 0...
July 2016: Tissue Barriers
https://www.readbyqxmd.com/read/27573048/current-treatments-for-advanced-melanoma-and-introduction-of-a-promising-novel-gene-therapy-for-melanoma-review
#17
Jae-Rim Heo, Nam-Hyung Kim, Jaejin Cho, Kyung-Chul Choi
Metastatic melanoma is a fatal form of skin cancer that has a tendency to proliferate more rapidly than any other solid tumor. Since 2010, treatment options for metastatic melanoma have been developed including chemotherapies, checkpoint inhibition immunotherapies, e.g., anti‑cytotoxic T‑lymphocyte antigen‑4 (CTLA‑4) and anti‑programmed death‑1 (PD‑1), and molecular-targeted therapies, e.g., BRAF and MEK inhibitors. These treatments have shown not only high response rates yet also side‑effects and limitations...
October 2016: Oncology Reports
https://www.readbyqxmd.com/read/27569556/metastatic-melanoma-insights-into-the-evolution-of-the-treatments-and-future-challenges
#18
REVIEW
Antoine Millet, Anthony R Martin, Cyril Ronco, Stéphane Rocchi, Rachid Benhida
Melanoma is the deadliest form of skin cancer. While associated survival prognosis is good when diagnosed early, it dramatically drops when melanoma progresses into its metastatic form. Prior to 2011, the favored therapies include interleukin-2 and chemotherapies, regardless of their low efficiency and their toxicity. Following key biological findings, two new types of therapy have been approved. First, there are the targeted therapies, which rely on small molecule B-Raf and MEK inhibitors and allow the treatment of patients with B-Raf mutated melanoma...
January 2017: Medicinal Research Reviews
https://www.readbyqxmd.com/read/27461037/the-promise-of-molecularly-targeted-and-immunotherapy-for-advanced-melanoma
#19
REVIEW
Kim Margolin
Advanced melanoma, rarely diagnosed at the time of primary melanoma excision but most often occurring later via lymphatic or hematogenous dissemination, is the cause of death for approximately 10,000 people in the USA each year, with the rate of incidence and death increasing yearly. Its causes are multifactorial and depend in large part on solar ultraviolet damage to DNA as well as underlying genetic predisposition. Cutaneous melanoma is the most common, but other subsets of importance are mucosal and uveal primaries, with different biology and treatment considerations...
September 2016: Current Treatment Options in Oncology
https://www.readbyqxmd.com/read/27447748/fatal-gastrointestinal-toxicity-with-ipilimumab-after-braf-mek-inhibitor-combination-in-a-melanoma-patient-achieving-pathological-complete-response
#20
Maria Gonzalez-Cao, Aram Boada, Cristina Teixidó, María Teresa Fernandez-Figueras, Clara Mayo, Francesc Tresserra, Jean Bustamante, Santiago Viteri, Enrique Puertas, Mariacarmela Santarpia, Aldo Riso, Feliciano Barron, Niki Karachaliou, Rafael Rosell
Approximately 50% of metastatic melanoma patients harbor BRAF mutations. Several treatment options including the combination of BRAF and MEK inhibitors (BRAF/MEKi) and immunotherapy (mainly anti CTLA-4 and anti PD-1 antibodies), have been shown to improve survival in these patients. Although preclinical data support the synergistic effect of both modalities in combination, data confirming the activity and tolerability of these combinations are not yet available in the clinical setting. Herein, we report the case of a melanoma patient treated with sequential BRAF/MEKi (dabrafenib plus trametinib) followed by the anti CTLA-4 antibody ipilimumab who achieved a pathological complete response...
August 30, 2016: Oncotarget
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