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https://www.readbyqxmd.com/read/27905110/distinct-molecular-landscapes-between-endometrioid-and-non-endometrioid-uterine-carcinomas
#1
Nathaniel L Jones, Joanne Xiu, Sudeshna Chatterjee-Paer, Alexandre Buckley de Meritens, William M Burke, Ana I Tergas, Jason D Wright, June Y Hou
Endometrial carcinoma (EC) is traditionally characterized as endometrioid and non-endometrioid based on histo-pathologic phenotypes. Molecular-based classifications have been proposed, but are not widely implemented. Herein we examine molecular profiles between EC histologic subtypes. 3133 ECs were submitted between March 2011 and July 2014: 1634 Type I and 1226 Type II. In situ hybridization and immunohistochemistry were used to assess copy number and protein expression of selected genes. Sequenced variants in 47 genes were analyzed using the Illumina TruSeq Amplicon Cancer Panel...
December 1, 2016: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/27900807/highly-ortho-selective-chlorination-of-anilines-using-a-secondary-ammonium-salt-organocatalyst
#2
Xiaodong Xiong, Ying-Yeung Yeung
An organocatalytic, highly facile, efficient, and regioselective ortho-chlorination of anilines is described. A secondary ammonium chloride salt has been employed as the catalyst and the reaction can be conducted at room temperature without protection from air and moisture. In addition, the reaction is readily scalable and the catalyst can be recycled and reused. This catalytic protocol has been applied to the efficient synthesis of a highly potent c-Met kinase inhibitor. Mechanistic studies revealed that unique structural features of the secondary ammonium chloride salt are important for both the catalysis and regioselectivity of the electrophilic ortho-chlorination...
November 30, 2016: Angewandte Chemie
https://www.readbyqxmd.com/read/27896243/profile-of-tivantinib-and-its-potential-in-the-treatment-of-hepatocellular-carcinoma-the-evidence-to-date
#3
REVIEW
Daniel Pievsky, Nikolaos Pyrsopoulos
Hepatocellular carcinoma (HCC) is the fastest rising cause of cancer-related death in the United States and carries a very poor prognosis, with a median survival time of <50% at 1 year for advanced disease. To date, sorafenib is the only therapy approved by the Food and Drug Administration for the treatment of advanced HCC. Tivantinib (ARQ-197), a non-ATP competitive inhibitor of cellular mesenchymal-epithelial transcription factor (c-MET), has shown a survival benefit in patients with advanced HCC who have failed or are intolerant to sorafenib in Phase I and II trials...
2016: Journal of Hepatocellular Carcinoma
https://www.readbyqxmd.com/read/27894094/met-expression-and-copy-number-status-in-clear-cell-renal-cell-carcinoma-prognostic-value-and-potential-predictive-marker
#4
Stephan Macher-Goeppinger, Martina Keith, Volker Endris, Roland Penzel, Katrin E Tagscherer, Sascha Pahernik, Markus Hohenfellner, Humphrey Gardner, Carsten Grüllich, Peter Schirmacher, Wilfried Roth
Multiple targeted therapy for advanced clear-cell renal cell carcinoma (RCC) has substantially improved patient outcome, but complete remission is uncommon and many tumors eventually develop resistance. Mechanistic, preclinical, and early clinical data highlight c-Met / hepatocyte growth factor receptor as a promising target for RCC therapeutic agents.We have examined MET expression, frequency of MET gene copy gains and MET gene mutation in a large, hospital-based series of renal cell carcinomas with long-term follow-up information...
November 24, 2016: Oncotarget
https://www.readbyqxmd.com/read/27893712/blood-vessel-endothelium-directed-tumor-cell-streaming-in-breast-tumors-requires-the-hgf-c-met-signaling-pathway
#5
E Leung, A Xue, Y Wang, P Rougerie, V P Sharma, R Eddy, D Cox, J Condeelis
During metastasis to distant sites, tumor cells migrate to blood vessels. In vivo, breast tumor cells utilize a specialized mode of migration known as streaming, where a linear assembly of tumor cells migrate directionally towards blood vessels on fibronectin-collagen I-containing extracellular matrix (ECM) fibers in response to chemotactic signals. We have successfully reconstructed tumor cell streaming in vitro by co-plating tumors cells, macrophages and endothelial cells on 2.5 μm thick ECM-coated micro-patterned substrates...
November 28, 2016: Oncogene
https://www.readbyqxmd.com/read/27880942/acquired-resistance-to-braf-inhibition-induces-epithelial-to-mesenchymal-transition-in-braf-v600e-mutant-thyroid-cancer-by-c-met-mediated-akt-activation
#6
Hyung Kwon Byeon, Hwi Jung Na, Yeon Ju Yang, Sooah Ko, Sun Och Yoon, Minhee Ku, Jaemoon Yang, Jae Wook Kim, Myung Jin Ban, Ji-Hoon Kim, Da Hee Kim, Jung Min Kim, Eun Chang Choi, Chang-Hoon Kim, Joo-Heon Yoon, Yoon Woo Koh
Previously, the authors have identified that c-Met mediates reactivation of the PI3K/AKT pathway following BRAF inhibitor treatment in BRAF (V600E) mutant anaplastic thyroid cancer, thereby contributing to the acquired drug resistance. Therefore dual inhibition of BRAF and c-Met led to sustained treatment response, thereby maximizing the specific anti-tumor effect of targeted therapy. The present study goes one step further and aims to investigate the effect of acquired resistance of BRAF inhibitor on epithelial-to-mesenchymal transition (EMT) in BRAF mutant thyroid cancer cells and the effect of dual inhibition from combinatorial therapy...
November 21, 2016: Oncotarget
https://www.readbyqxmd.com/read/27879272/quantification-of-pathway-crosstalk-reveals-novel-synergistic-drug-combinations-for-breast-cancer
#7
Samira Jaeger, Ana Igea, Rodrigo Arroyo, Victor Alcalde, Begoña Canovas, Modesto Orozco, Angel R Nebreda, Patrick Aloy
Combinatorial therapeutic approaches are an imperative to improve cancer treatment, since it is critical to impede compensatory signaling mechanisms that can engender drug resistance to individual targeted drugs. Currently approved drug combinations result largely from empirical clinical experience and cover only a small fraction of a vast therapeutic space. Here we present a computational network biology approach, based on pathway crosstalk inhibition, to discover new synergistic drug combinations for breast cancer treatment...
November 22, 2016: Cancer Research
https://www.readbyqxmd.com/read/27864331/role-of-sphingosine-kinase-1-and-s1p-transporter-spns2-in-hgf-mediated-lamellipodia-formation-in-lung-endothelium
#8
Panfeng Fu, David L Ebenezer, Evgeny V Berdyshev, Irina A Bronova, Mark Shaaya, Anantha Harijith, Viswanathan Natarajan
Hepatocyte growth factor (HGF) signaling via c-Met is known to promote endothelial cell motility and angiogenesis. We have previously reported that HGF stimulates lamellipodia formation and motility of human lung microvascular endothelial cells (HLMVECs) via PI3k/Akt signal transduction and reactive oxygen species generation. Here, we report a role for HGF-induced intracellular sphingosine-1-phosphate (S1P) generation catalyzed by sphingosine kinase 1 (SphK1), S1P transporter, spinster homolog 2 (Spns2), and S1P receptor, S1P1, in lamellipodia formation and perhaps motility of HLMVECs...
November 18, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27853643/peritumoral-stromal-neutrophils-are-essential-for-c-met-elicited-metastasis-in-human-hepatocellular-carcinoma
#9
Min He, Anping Peng, Xian-Zhang Huang, Dai-Chao Shi, Jun-Cheng Wang, Qiyi Zhao, Haibiao Lin, Dong-Ming Kuang, Pei-Feng Ke, Xiang-Ming Lao
Inflammation is a component of tumor progression mechanisms. Neutrophils are a common inflammatory infiltrate in many tumors, but their regulation and functions in neoplasia are not understood. Here, we showed, in detailed studies of c-Met molecule in 225 untreated patients with hepatocellular carcinoma (HCC), that high infiltration of neutrophils in HCC tissues determined malignant cell c-Met-associated clinical outcome of patients. High infiltration of neutrophils in HCCs determined malignant cell c-Met-associated clinical outcome of patients...
2016: Oncoimmunology
https://www.readbyqxmd.com/read/27849399/new-chemical-treatment-options-in-second-line-hepatocellular-carcinoma-what-to-do-when-sorafenib-fails
#10
Hyun Young Woo, So Young Yoo, Jeong Heo
There have been no therapies available for patients who experience disease progression after sorafenib treatment. Regorafenib inhibits multiple kinases involved in tumor proliferation and neoangiogenesis, which has produced a survival benefit in hepatocellular carcinoma (HCC) after sorafenib failure. Other active candidate agents are c-Met inhibitors and immune checkpoint inhibitors. Areas covered: This paper presents an updated summary of the preclinical and clinical experience with regorafenib, c-Met inhibitors (tivantinib, cabozantinib and tepotinib), and a checkpoint inhibitor (nivolumab, pembrolizumab) in HCC...
November 28, 2016: Expert Opinion on Pharmacotherapy
https://www.readbyqxmd.com/read/27844272/resistance-to-targeted-therapies-in-renal-cancer-the-importance-of-changing-the-mechanism-of-action
#11
I Duran, J Lambea, P Maroto, J L González-Larriba, Luis Flores, S Granados-Principal, M Graupera, B Sáez, A Vivancos, O Casanovas
Renal cell carcinoma (RCC) is a complex disease characterized by mutations in several genes. Loss of function of the von Hippel-Lindau (VHL) tumour suppressor gene is a very common finding in RCC and leads to up-regulation of hypoxia-inducible factor (HIF)-responsive genes accountable for angiogenesis and cell growth, such as platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF). Binding of these proteins to their cognate tyrosine kinase receptors on endothelial cells promotes angiogenesis...
November 15, 2016: Targeted Oncology
https://www.readbyqxmd.com/read/27843623/phase-ii-study-of-erlotinib-plus-tivantinib-arq-197-in-patients-with-locally-advanced-or-metastatic-egfr-mutation-positive-non-small-cell-lung-cancer-just-after-progression-on-egfr-tki-gefitinib-or-erlotinib
#12
Koichi Azuma, Tomonori Hirashima, Nobuyuki Yamamoto, Isamu Okamoto, Toshiaki Takahashi, Makoto Nishio, Taizo Hirata, Kaoru Kubota, Kazuo Kasahara, Toyoaki Hida, Hiroshige Yoshioka, Kaoru Nakanishi, Shiro Akinaga, Kazuto Nishio, Tetsuya Mitsudomi, Kazuhiko Nakagawa
BACKGROUND: Patients with epidermal growth factor receptor (EGFR) activation mutation-positive non-small-cell lung cancer (NSCLC) respond well to EGFR tyrosine kinase inhibitors (EGFR-TKIs), but eventually become resistant in most cases. The hepatocyte growth factor/c-Met (HGF/c-Met) pathway is reported as a poor prognostic factor in various cancers. As c-Met is involved in EGFR-TKI resistance, a c-Met inhibitor and EGFR-TKI combination may reverse the resistance. This study evaluated the efficacy and safety of a c-Met selective inhibitor, tivantinib (ARQ 197), in combination with erlotinib, in Japanese EGFR mutation-positive patients with NSCLC who progressed while on EGFR-TKIs...
2016: ESMO Open
https://www.readbyqxmd.com/read/27843150/the-bacterial-peptidoglycan-sensing-molecule-pglyrp2-modulates-brain-development-and-behavior
#13
T Arentsen, Y Qian, S Gkotzis, T Femenia, T Wang, K Udekwu, H Forssberg, R Diaz Heijtz
Recent studies have revealed that the gut microbiota modulates brain development and behavior, but the underlying mechanisms are still poorly understood. Here, we show that bacterial peptidoglycan (PGN) derived from the commensal gut microbiota can be translocated into the brain and sensed by specific pattern-recognition receptors (PRRs) of the innate immune system. Using expression-profiling techniques, we demonstrate that two families of PRRs that specifically detect PGN (that is, PGN-recognition proteins and NOD-like receptors), and the PGN transporter PepT1 are highly expressed in the developing brain during specific windows of postnatal development in both males and females...
November 15, 2016: Molecular Psychiatry
https://www.readbyqxmd.com/read/27822425/neat1-regulates-pancreatic-cancer-cell-growth-invasion-and-migration-though-mircrorna-335-5p-c-met-axis
#14
Jia Cao, Yi Zhang, Jiachun Yang, Sijia He, Mingming Li, Shiyan Yan, Ying Chen, Chunying Qu, Leiming Xu
NEAT1 has been reported to affect cancer progression, which was subsequently confirmed in multiple cancers. Hsa-miRNA-335-5p (miR-335-5p) has recently been identified as an anticancer agent in various organs. However, the relationship between NEAT1 and miR-335-5p remains poorly understood. In this study, we investigated the effects of NEAT1 and miR-335-5p on development of pancreatic cancer. The ectopic expression of miR-335-5p in pancreatic cancer cell lines significantly suppressed cell growth by inhibiting c-met...
2016: American Journal of Cancer Research
https://www.readbyqxmd.com/read/27816491/the-noni-anthraquinone-damnacanthal-is-a-multi-kinase-inhibitor-with-potent-anti-angiogenic-effects
#15
Javier A García-Vilas, Almudena Pino-Ángeles, Beatriz Martínez-Poveda, Ana R Quesada, Miguel Ángel Medina
The natural bioactive compound damnacanthal inhibits several tyrosine kinases. Herein, we show that -in fact- damancanthal is a multi kinase inhibitor. A docking and molecular dynamics simulation approach allows getting further insight on the inhibitory effect of damnacanthal on three different kinases: vascular endothelial growth factor receptor-2, c-Met and focal adhesion kinase. Several of the kinases targeted and inhibited by damnacanthal are involved in angiogenesis. Ex vivo and in vivo experiments clearly demonstrate that, indeed, damnacanthal is a very potent inhibitor of angiogenesis...
November 2, 2016: Cancer Letters
https://www.readbyqxmd.com/read/27810404/in%C3%A2-vivo-targeting-of-c-met-using-a-non-standard-macrocyclic-peptide-in-gastric-carcinoma
#16
Do Won Hwang, Namryeong Bahng, Kenichiro Ito, Seunggyun Ha, Mee Young Kim, Eunji Lee, Hiroaki Suga, Dong Soo Lee
Development of c-Met targeting probes based on specifically designed peptides with high affinity and stability could help enhance diagnostic efficacy and therapeutic effects in c-Met positive cancers. The Random non-standard Peptides Integrated Discovery (RaPID) system for synthesizing natural product-like macrocyclic peptides via in vitro translation-based selection has recently emerged to overcome the shortcomings of traditional peptide synthesis. Here, we developed non-standard macrocyclic peptides specific to c-Met, and examined the cancer-targeting efficiency of fluorescein-labeled (FL) anti-c-Met peptides, referred to as aML5-FL and aMD4-FL, both in vitro and in vivo...
October 31, 2016: Cancer Letters
https://www.readbyqxmd.com/read/27804876/recent-advances-on-the-design-and-synthesis-of-c-met-inhibitors-as-anticancer-agents-2014-present
#17
Peng-Cheng Lv, Zhong-Chang Wang, Hai-Liang Zhu
c-Met, also known as the surface receptor of hepatocyte growth factor receptor (HGFR), is a receptor tyrosine kinase with heterodimeric transmembrane. c-Met involves in the activation of several signaling pathways, most of which are implicated in aggressive cancer phenotypes. In a variety of human malignances, c-Met/HGF signaling has been found aberrant, and in many instances has been correlated with advanced disease stage and poor prognosis. Thus, the c-Met has identified as an emerging and interesting target for cancer chemotherapy...
October 28, 2016: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/27804848/novel-1-2-4-triazol-4-3-a-pyridine-derivatives-as-potential-selective-c-met-inhibitors-with-improved-pharmacokinetic-properties
#18
Junjun Zhao, Shaohua Gou, Xiaobing Zhang, Yan Liang, Lei Fang
Total twenty-nine [1,2,4]triazolo[4,3-a]pyrazine derivatives were designed and synthesized. The target compounds, especially 4aa, showed potent activity to inhibit c-Met both in an enzyme assay and a cellular assay. The comprehensive screening for the inhibition of 60 different kinases revealed that 4aa could selectively inhibit c-Met while had no effect on other kinases, indicating 4aa is an excellent c-Met selective inhibitor. The flow cytometry studies found that 4aa had a similar behavior to the positive control SGX-523 in the terms of causing the tumor cell apoptosis and blocking cell-cycle progression...
October 31, 2016: Anti-cancer Agents in Medicinal Chemistry
https://www.readbyqxmd.com/read/27793046/transcriptional-upregulation-of-c-met-is-associated-with-invasion-and-tumor-budding-in-colorectal-cancer
#19
Conor A Bradley, Philip D Dunne, Victoria Bingham, Stephen McQuaid, Hajrah Khawaja, Stephanie Craig, Jackie James, Wendy L Moore, Darragh G McArt, Mark Lawler, Sonali Dasgupta, Patrick G Johnston, Sandra Van Schaeybroeck
c-MET and its ligand HGF are frequently overexpressed in colorectal cancer (CRC) and increased c-MET levels are found in CRC liver metastases. This study investigated the role of the HGF/c-MET axis in regulating migration/invasion in CRC, using pre-clinical models and clinical samples. Pre-clinically, we found marked upregulation of c-MET at both protein and mRNA levels in several invasive CRC cells. Down-regulation of c-MET using RNAi suppressed migration/invasion of parental and invasive CRC cells. Stimulation of CRC cells with rh-HGF or co-culture with HGF-expressing colonic myofibroblasts, resulted in significant increases in their migratory/invasive capacity...
October 26, 2016: Oncotarget
https://www.readbyqxmd.com/read/27790245/associations-of-mrna-microrna-for-the-shared-downstream-molecules-of-egfr-and-alternative-tyrosine-kinase-receptors-in-non-small-cell-lung-cancer
#20
Fengfeng Wang, Fei Meng, Lili Wang, S C Cesar Wong, William C S Cho, Lawrence W C Chan
Lung cancer is the top cancer killer worldwide with high mortality rate. Majority belong to non-small cell lung cancers (NSCLCs). The epidermal growth factor receptor (EGFR) has been broadly explored as a drug target for therapy. However, the drug responses are not durable due to the acquired resistance. MicroRNAs (miRNAs) are small non-coding and endogenous molecules that can inhibit mRNA translation initiation and degrade mRNAs. We wonder if some downstream molecules shared by EGFR and the other tyrosine kinase receptors (TKRs) further transduce the signals alternatively, and some miRNAs play the key roles in affecting the expression of these downstream molecules...
2016: Frontiers in Genetics
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