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https://www.readbyqxmd.com/read/27885740/asp5878-a-selective-fgfr-inhibitor-to-treat-fgfr3-dependent-urothelial-cancer-with-or-without-chemoresistance
#1
Aya Kikuchi, Tomoyuki Suzuki, Taisuke Nakazawa, Masateru Iizuka, Ayako Nakayama, Tohru Ozawa, Minoru Kameda, Nobuaki Shindoh, Tadashi Terasaka, Masaaki Hirano, Sadao Kuromitsu
FGF/FGFR gene aberrations such as amplification, mutation and fusion are associated with many types of human cancers including urothelial cancer. FGFR kinase inhibitors are expected to be a targeted therapy for urothelial cancer harboring FGFR3 gene alternations. ASP5878, a selective inhibitor of FGFR1, 2, 3 and 4 under clinical investigation, selectively inhibited cell proliferation of urothelial cancer cell lines harboring FGFR3 point mutation or fusion (UM-UC-14, RT-112, RT4 and SW 780) among 23 urothelial cancer cell lines...
November 25, 2016: Cancer Science
https://www.readbyqxmd.com/read/27870574/evaluation-of-bgj398-a-fibroblast-growth-factor-receptor-1-3-kinase-inhibitor-in-patients-with-advanced-solid-tumors-harboring-genetic-alterations-in-fibroblast-growth-factor-receptors-results-of-a-global-phase-i-dose-escalation-and-dose-expansion-study
#2
Lucia Nogova, Lecia V Sequist, Jose Manuel Perez Garcia, Fabrice Andre, Jean-Pierre Delord, Manuel Hidalgo, Jan H M Schellens, Philippe A Cassier, D Ross Camidge, Martin Schuler, Ulka Vaishampayan, Howard Burris, G Gary Tian, Mario Campone, Zev A Wainberg, Wan-Teck Lim, Patricia LoRusso, Geoffrey I Shapiro, Katie Parker, Xueying Chen, Somesh Choudhury, Francois Ringeisen, Diana Graus-Porta, Dale Porter, Randi Isaacs, Reinhard Buettner, Jürgen Wolf
Purpose This two-part, first-in-human study was initiated in patients with advanced solid tumors harboring genetic alterations in fibroblast growth factor receptors (FGFRs) to determine the maximum tolerated dose (MTD), the recommended phase II dose (RP2D), and the schedule, safety, pharmacokinetics, pharmacodynamics, and antitumor activity of oral BGJ398, a selective FGFR1-3 tyrosine kinase inhibitor. Patients and Methods Adult patients were treated with escalating dosages of BGJ398 5 to 150 mg once daily or 50 mg twice daily continuously in 28-day cycles...
November 21, 2016: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/27857023/fgfr4-arg388-is-correlated-with-poor-survival-in-resected-colon-cancer-promoting-epithelial-to-mesenchymal-transition
#3
Sang Hee Cho, Chang Soo Hong, Hee Nam Kim, Min Ho Shin, Ka Rham Kim, Hyun Jeong Shim, Jun Eul Hwang, Woo Kyun Bae, Ik Joo Chung
Purpose: Fibroblast growth factor receptor (FGFR) 4 plays an important role in cancer progression during tumor proliferation, invasion, and metastasis. This study evaluated the prognostic role of FGFR4 polymorphism in patients with resected colon cancer, including the underlying mechanism. Materials and Methods: FGFR4 polymorphism was characterized in patients who received curative resection for stage III colon cancer. FGFR4-dependent signal pathways involving cell proliferation, invasion, and migration according to genotypes were also evaluated in transfected colon cancer cell lines...
November 9, 2016: Cancer Research and Treatment: Official Journal of Korean Cancer Association
https://www.readbyqxmd.com/read/27852792/fgfr-tacc-gene-fusions-in-human-glioma
#4
REVIEW
Anna Lasorella, Marc Sanson, Antonio Iavarone
Chromosomal translocations joining in-frame members of the fibroblast growth factor receptor-transforming acidic coiled-coil gene families (the FGFR-TACC gene fusions) were first discovered in human glioblastoma multiforme (GBM) and later in many other cancer types. Here, we review this rapidly expanding field of research and discuss the unique biological and clinical features conferred to isocitrate dehydrogenase wild-type glioma cells by FGFR-TACC fusions. FGFR-TACC fusions generate powerful oncogenes that combine growth-promoting effects with aneuploidy through the activation of as yet unclear intracellular signaling mechanisms...
November 16, 2016: Neuro-oncology
https://www.readbyqxmd.com/read/27837028/asp5878-a-novel-inhibitor-of-fgfr-1-2-3-and-4-inhibits-the-growth-of-fgf19-expressing-hepatocellular-carcinoma
#5
Takashi Futami, Hidetsugu Okada, Rumi Kihara, Tatsuya Kawase, Ayako Nakayama, Tomoyuki Suzuki, Minoru Kameda, Nobuaki Shindoh, Tadashi Terasaka, Masaaki Hirano, Sadao Kuromitsu
Hepatocellular carcinoma is an aggressive cancer with poor prognosis. Fibroblast growth factor 19, a member of the fibroblast growth factor family, is a ligand for fibroblast growth factor receptor 4. Moreover, it plays a crucial role in the progression of hepatocellular carcinoma. ASP5878 is a novel inhibitor of fibroblast growth factor receptors 1, 2, 3, and 4 that is under development. It inhibits fibroblast growth factor receptor 4 kinase activity with an IC50 of 3.5 nmol/L. ASP5878 potently suppressed the growth of the fibroblast growth factor 19-expressing hepatocellular carcinoma cell lines Hep3B2...
November 11, 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27825137/fgfr-signaling-maintains-a-drug-persistent-cell-population-following-epithelial-mesenchymal-transition
#6
Wells S Brown, Saeed Salehin Akhand, Michael K Wendt
An emerging characteristic of drug resistance in cancer is the induction of epithelial-mesenchymal transition (EMT). However, the mechanisms of EMT-mediated drug resistance remain poorly defined. Therefore, we conducted long-term treatments of human epidermal growth factor receptor-2 (Her2)-transformed breast cancer cells with either the EGFR/Her2 kinase inhibitor, Lapatinib or TGF-β, a known physiological inducer of EMT. Both of these treatment regimes resulted in robust EMT phenotypes, but upon withdrawal a subpopulation of TGF-β induced cells readily underwent mesenchymal-epithelial transition, where as Lapatinib-induced cells failed to reestablish an epithelial population...
November 4, 2016: Oncotarget
https://www.readbyqxmd.com/read/27817859/-lenvatinib-in-radioiodine-refractory-thyroid-carcinomas
#7
Christelle de la Fouchardiere
Differentiated thyroid cancers are usually cured by an appropriate surgery and a radioiodine remnant ablation. If metastases occur, successive radioiodine administrations and/or local treatments can be provided. Nevertheless, some patients will be, or become refractory to radioiodine. In case of significant and rapid progression of metastatic lesions, they will be candidate to kinase inhibitor treatments. Two agents are now approved in this situation: sorafenib and lenvatinib. Lenvatinib (Lenvima(®)) is a tyrosine kinase inhibitor (TKI) targeting the VEGFR1-3, FGFR 1-4, PDGFR-α, RET and c-kit...
November 3, 2016: Bulletin du Cancer
https://www.readbyqxmd.com/read/27802183/prognostic-impact-of-fibroblast-growth-factor-receptor-2-gene-amplification-in-patients-receiving-fluoropyrimidine-and-platinum-chemotherapy-for-metastatic-and-locally-advanced-unresectable-gastric-cancers
#8
Seyoung Seo, Seong Joon Park, Min-Hee Ryu, Sook Ryun Park, Baek-Yeol Ryoo, Young Soo Park, Young-Soon Na, Chae-Won Lee, Ju-Kyung Lee, Yoon-Koo Kang
Although Fibroblast growth factor receptor (FGFR) 2 gene amplification and its prognostic significance have been reported in resectable gastric cancers, information on these features remains limited in the metastatic setting. The presence of FGFR2 amplification was assessed in formalin-fixed, paraffin-embedded tissues using a quantitative PCR-based gene copy number assay with advanced gastric cancer cohorts. A total of 327 patients with tumor portion of ≥70% were analyzed for clinical features. Among these patients, 260 who received first-line fluoropyrimidine and platinum chemotherapy were analyzed for survival...
October 27, 2016: Oncotarget
https://www.readbyqxmd.com/read/27794612/phosphoproteome-profiling-reveals-molecular-mechanisms-of-growth-factor-mediated-kinase-inhibitor-resistance-in-egfr-overexpressing-cancer-cells
#9
Heiner Koch, Mathias Wilhelm, Benjamin Ruprecht, Scarlet Beck, Martin Frejno, Susan Klaeger, Bernhard Kuster
Although substantial progress has been made regarding the use of molecularly targeted cancer therapies, resistance almost invariably develops and presents a major clinical challenge. The tumor microenvironment can rescue cancer cells from kinase inhibitors by growth factor mediated induction of pro-survival pathways. Here, we show that EGFR inhibition by Gefitinib is counteracted by growth factors notably FGF2 and we assessed the global molecular consequences of this resistance at the proteome and phosphoproteome level in A431 cells...
October 30, 2016: Journal of Proteome Research
https://www.readbyqxmd.com/read/27794399/combination-effects-of-arsenic-trioxide-and-fibroblast-growth-factor-receptor-inhibitor-in-squamous-cell-lung-carcinoma
#10
Sze-Kwan Lam, Leanne Lee Leung, Yuan-Yuan Li, Chun-Yan Zheng, James Chung-Man Ho
OBJECTIVES: Lung cancer remains the top cancer killer worldwide, with squamous cell carcinoma (SCC) as the second commonest histologic subtype. Arsenic trioxide (ATO) was previously shown to suppress growth of lung cancer. Fibroblast growth factor receptor (FGFR) amplification was recently demonstrated in lung SCC, with specific FGFR inhibitor (e.g. PD173074) developed as a potential targeted therapy. Therefore the combination effects of ATO and PD173074 in SCC was studied. MATERIALS AND METHODS: The combination of ATO/PD173074 was studied in a proof-of-principle model using a lung SCC cell line with FGFR1 overexpression: SK-MES-1...
November 2016: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/27785367/fgfr1-2-and-3-protein-overexpression-and-molecular-aberrations-of-fgfr3-in-early-stage-non-small-cell-lung-cancer
#11
Willemijn Sme Theelen, Lorenza Mittempergher, Stefan M Willems, Astrid J Bosma, Dennis Dgc Peters, Vincent van der Noort, Eva J Japenga, Ton Peeters, Koos Koole, Tonći Šuštić, J L Blaauwgeers, Carel J van Noesel, René Bernards, Michel M van den Heuvel
This study aimed to determine protein expression levels of fibroblast growth factor receptors (FGFR) 1, 2 and 3 in early stage non-small cell lung cancer (NSCLC). Additionally, a screen to define the frequency of FGFR3-TACC3 translocation and FGFR3 amplification was performed. Archived tissues from 653 NSCLC samples (adenocarcinoma (AC), squamous cell carcinoma (SCC) and large cell carcinoma (LCC)) were analysed with immunohistochemistry (IHC) for expression of FGFR1, 2 and 3. Expression levels of FGFR1, 2 and 3 were correlated with clinicopathological features...
October 2016: Journal of Pathology. Clinical Research
https://www.readbyqxmd.com/read/27783942/dual-targeting-of-pdgfr%C3%AE-and-fgfr1-displays-synergistic-efficacy-in-malignant-rhabdoid-tumors
#12
Jocelyn P Wong, Jason R Todd, Martina A Finetti, Frank McCarthy, Malgorzata Broncel, Simon Vyse, Maciej T Luczynski, Stephen Crosier, Karen A Ryall, Kate Holmes, Leo S Payne, Frances Daley, Patty Wai, Andrew Jenks, Barbara Tanos, Aik-Choon Tan, Rachael C Natrajan, Daniel Williamson, Paul H Huang
Subunits of the SWI/SNF chromatin remodeling complex are mutated in a significant proportion of human cancers. Malignant rhabdoid tumors (MRTs) are lethal pediatric cancers characterized by a deficiency in the SWI/SNF subunit SMARCB1. Here, we employ an integrated molecular profiling and chemical biology approach to demonstrate that the receptor tyrosine kinases (RTKs) PDGFRα and FGFR1 are coactivated in MRT cells and that dual blockade of these receptors has synergistic efficacy. Inhibitor combinations targeting both receptors and the dual inhibitor ponatinib suppress the AKT and ERK1/2 pathways leading to apoptosis...
October 25, 2016: Cell Reports
https://www.readbyqxmd.com/read/27782099/design-synthesis-and-biological-evaluation-of-6-2-6-dichloro-3-5-dimethoxyphenyl-4-substituted-1h-indazoles-as-potent-fibroblast-growth-factor-receptor-inhibitors
#13
Zhen Zhang, Dongmei Zhao, Yang Dai, Maosheng Cheng, Meiyu Geng, Jingkang Shen, Yuchi Ma, Jing Ai, Bing Xiong
Tyrosine kinase fibroblast growth factor receptor (FGFR), which is aberrant in various cancer types, is a promising target for cancer therapy. Here we reported the design, synthesis, and biological evaluation of a new series of 6-(2,6-dichloro-3,5-dimethoxyphenyl)-4-substituted-1H-indazole derivatives as potent FGFR inhibitors. The compound 6-(2,6-dichloro-3,5-dimethoxyphenyl)-N-phenyl-1H-indazole-4-carboxamide (10a) was identified as a potent FGFR1 inhibitor, with good enzymatic inhibition. Further structure-based optimization revealed that 6-(2,6-dichloro-3,5-dimethoxyphenyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1H-indazole-4-carboxamide (13a) is the most potent FGFR1 inhibitor in this series, with an enzyme inhibitory activity IC50 value of about 30...
October 23, 2016: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/27750146/discovery-of-novel-ponatinib-analogues-for-reducing-kdr-activity-as-potent-fgfrs-inhibitors
#14
Yang Liu, Xia Peng, Xiaocong Guan, Dong Lu, Yong Xi, Shiyu Jin, Hui Chen, Limin Zeng, Jing Ai, Meiyu Geng, Youhong Hu
FGF receptors (FGFRs) are tyrosine kinases that are overexpressed in diverse tumors by genetic alterations such as gene amplifications, somatic mutations and translocations. Owing to this characteristic, FGFRs are attractive targets for cancer treatment. It has been demonstrated that most multi-targeted, ATP competitive tyrosine kinase inhibitors are active against FGFRs as well as other kinases. The design of new and more selective inhibitors of FGFRs, which might be reduced off-target and side effects, is a difficult yet significant challenge...
October 4, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27747092/the-rise-of-the-fgfr-inhibitor-in-advanced-biliary-cancer-the-next-cover-of-time-magazine
#15
Sumera Rizvi, Mitesh J Borad
Cholangiocarcinomas (CCAs) are heterogeneous tumors arising from the biliary tract with features of cholangiocyte differentiation. CCAs are aggressive tumors with limited treatment options and poor overall survival. Only a subset of CCA patients with early stage disease can avail potentially curative treatment options. For advanced biliary tract tumors, currently there are limited effective treatment modalities. Recent advances have provided greater insight into the genomic landscape of CCAs. The fibroblast growth factor receptor (FGFR) pathway is involved in key cellular processes essential to survival and differentiation...
October 2016: Journal of Gastrointestinal Oncology
https://www.readbyqxmd.com/read/27747090/beyond-her2-recent-advances-and-future-directions-in-targeted-therapies-in-esophagogastric-cancers
#16
Jimmy Hwang
Esophagogastric cancers (EGCa) are a leading cause of cancer related mortality worldwide. It has been recognized that they represent heterogenous diseases based on histology and anatomy. However, it is also increasingly evident that these are diverse malignancies based on genetic alterations, and this is increasingly making these diseases amenable to targeted therapies. While epidermal growth factor receptor (EGFR) and mTOR inhibitors have failed to prove effective in the treatment of advanced EGCa, vascular endothelial growth factor (VEGF) inihibitor have now been demonstrated to improve survival, at least in the 2nd line setting of adenocarcinomas...
October 2016: Journal of Gastrointestinal Oncology
https://www.readbyqxmd.com/read/27743530/targeting-fibroblast-growth-factor-receptors-and-immune-checkpoint-inhibitors-for-the-treatment-of-advanced-bladder-cancer-new-direction-and-new-hope
#17
Rafael Morales-Barrera, Cristina Suárez, Ana Martínez de Castro, Fabricio Racca, Claudia Valverde, Xavier Maldonado, Juan Maria Bastaros, Juan Morote, Joan Carles
Bladder cancer is one of the leading causes of death in Europe and the United States. About 25% of patients with bladder cancer have advanced disease (muscle-invasive or metastatic disease) at presentation and are candidates for systemic chemotherapy. In the setting of metastatic disease, use of cisplatin-based regimens improves survival. However, despite initial high response rates, the responses are typically not durable leading to recurrence and death in the vast majority of these patients with median overall survival of 15months and a 5-year survival rate of ⩽10%...
October 1, 2016: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/27741505/wide-spetcrum-mutational-analysis-of-metastatic-renal-cell-cancer-a-retrospective-next-generation-sequencing-approach
#18
Michelangelo Fiorentino, Elisa Gruppioni, Francesco Massari, Francesca Giunchi, Annalisa Altimari, Chiara Ciccarese, Davide Bimbatti, Aldo Scarpa, Roberto Iacovelli, Camillo Porta, Sarhadi Virinder, Giampaolo Tortora, Walter Artibani, Riccardo Schiavina, Andrea Ardizzoni, Matteo Brunelli, Sakari Knuutila, Guido Martignoni
Renal cell cancer (RCC) is characterized by histological and molecular heterogeneity that may account for variable response to targeted therapies. We evaluated retrospectively with a next generation sequencing (NGS) approach using a pre-designed cancer panel the mutation burden of 32 lesions from 22 metastatic RCC patients treated with at least one tyrosine kinase or mTOR inhibitor. We identified mutations in the VHL, PTEN, JAK3, MET, ERBB4, APC, CDKN2A, FGFR3, EGFR, RB1, TP53 genes. Somatic alterations were correlated with response to therapy...
October 10, 2016: Oncotarget
https://www.readbyqxmd.com/read/27694802/oligosaccharyltransferase-inhibition-induces-senescence-in-rtk-driven-tumor-cells
#19
Cecilia Lopez-Sambrooks, Shiteshu Shrimal, Carol Khodier, Daniel P Flaherty, Natalie Rinis, Jonathan C Charest, Ningguo Gao, Peng Zhao, Lance Wells, Timothy A Lewis, Mark A Lehrman, Reid Gilmore, Jennifer E Golden, Joseph N Contessa
Asparagine (N)-linked glycosylation is a protein modification critical for glycoprotein folding, stability, and cellular localization. To identify small molecules that inhibit new targets in this biosynthetic pathway, we initiated a cell-based high-throughput screen and lead-compound-optimization campaign that delivered a cell-permeable inhibitor, NGI-1. NGI-1 targets oligosaccharyltransferase (OST), a hetero-oligomeric enzyme that exists in multiple isoforms and transfers oligosaccharides to recipient proteins...
October 3, 2016: Nature Chemical Biology
https://www.readbyqxmd.com/read/27669755/fibroblast-growth-factor-receptor-fgfr-alterations-in-squamous-differentiated-bladder-cancer-a-putative-therapeutic-target-for-a-small-subgroup
#20
Philipp H Baldia, Angela Maurer, Timon Heide, Michael Rose, Robert Stoehr, Arndt Hartmann, Sarah V Williams, Margaret A Knowles, Ruth Knuechel, Nadine T Gaisa
Although drugable fibroblast growth factor receptor (FGFR) alterations in squamous cell carcinomas (SCC) of various entities are well known, little is known about FGFR modifications in squamous differentiated bladder cancer. Therefore, our study evaluated FGFR1-3 alterations as a putative therapeutic target in this subgroup. We analyzed 73 squamous differentiated bladder cancers (n = 10 pT2, n = 55 pT3, n = 8 pT4) for FGFR1-3 protein expression, FGFR1-3 copy number variations, FGFR3 chromosomal rearrangements (fluorescence in situ hybridization (FISH)) and FGFR3 mutations (SNapShot analysis)...
September 22, 2016: Oncotarget
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