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https://www.readbyqxmd.com/read/29223982/pazopanib-sensitivity-in-a-patient-with-breast-cancer-and-fgfr1-amplification
#1
Fiona Tsui-Fen Cheng, Fu Ou-Yang, Nina Lapke, Kai-Che Tung, Yen-Kung Chen, Yuh-Yu Chou, Shu-Jen Chen
Treatment options for patients with hormone receptor-positive (HR+), HER2-negative (HER2-) breast cancer and resistance to endocrine therapy remain limited. An interesting therapeutic target in these patients is fibroblast growth factor receptor 1 (FGFR1). FGFR1 is amplified in approximately 11% of patients with breast cancer, especially those with HR+ disease. This report presents a patient with metastatic HR+ HER2- breast cancer harboring an FGFR1 amplification who was resistant to endocrine therapy but responded to pazopanib, a multi-tyrosine kinase inhibitor with FGFR-inhibiting activity...
December 2017: Journal of the National Comprehensive Cancer Network: JNCCN
https://www.readbyqxmd.com/read/29222162/dual-inhibition-of-pik3c3-and-fgfr-as-a-new-therapeutic-approach-to-treat-bladder-cancer
#2
Chun-Han Chen, C Changou, Tsung-Han Hsieh, Yu-Ching Lee, Cheng-Ying Chu, Kai-Cheng Hsu, Hao-Ching Wang, Yu-Chen Lin, Yan-Ni Lo, Yun-Ru Liu, Jing-Ping Liou, Yun Yen
PURPOSE: MPT0L145 has been developed as a FGFR inhibitor exhibiting significant anti-bladder cancer activity in vitro and in vivo via promoting autophagy-dependent cell death. Here, we aim to elucidate the underlying mechanisms. EXPERIMENTAL DESIGN: Autophagy flux, morphology and intracellular organelles were evaluated by western blotting, transmission electron microscope and fluorescence microscope. Molecular docking, surface plasmon resonance assay were performed to identify drug-protein interaction...
December 8, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29217514/novel-ocular-toxicity-associated-with-fibroblast-growth-factor-receptor-fgfr-inhibitors-in-cancer-treatment-observational-case-series
#3
Daniel Velazquez-Villoria, Analia Azaro, Jordi Rodon, Cinta Hierro, Danai Kyriakou, Jose Garcia-Arumi, Miguel Angel Zapata
AIMS: To describe novel ocular toxicity in patients with metastatic cancer undergoing chemotherapy with fibroblast growth factor receptor (FGFR) inhibitors. METHODS: This observational case series study included five patients with advanced cancer who received selected pan-FGFR inhibitors as single chemotherapy in the framework of a dose-finding study and phase I and phase II clinical studies. In all cases, subfoveal neurosensory retinal detachment was diagnosed...
December 7, 2017: British Journal of Ophthalmology
https://www.readbyqxmd.com/read/29207153/fgfr-inhibitor-bgj398-and-hdac-inhibitor-obp-801-synergistically-inhibit-cell-growth-and-induce-apoptosis-in-bladder-cancer-cells
#4
Toshiya Takamura, Mano Horinaka, Shusuke Yasuda, Seijiro Toriyama, Yuichi Aono, Yoshihiro Sowa, Tsuneharu Miki, Osamu Ukimura, Toshiyuki Sakai
In advanced bladder cancer, cisplatin-based chemotherapy has been the standard treatment for many years, but there are many problems in terms of side-effects. Recently, a number of clinical trials using molecular-targeted agents have been conducted, and new therapies are expected that could replace conventional cytotoxic chemotherapy. We herein report that concurrent treatment with fibroblast growth factor receptor (FGFR) inhibitor BGJ398 and the novel histone deacetylase (HDAC) inhibitor OBP-801/YM753/spiruchostatin A synergistically inhibited cell growth and markedly induced apoptosis in high-grade bladder cancer cells...
December 1, 2017: Oncology Reports
https://www.readbyqxmd.com/read/29206199/a-novel-receptor-tyrosine-kinase-switch-promotes-gastrointestinal-stromal-tumor-drug-resistance
#5
Sergei Boichuk, Aigul Galembikova, Pavel Dunaev, Elena Valeeva, Elena Shagimardanova, Oleg Gusev, Svetlana Khaiboullina
The fact that most gastrointestinal stromal tumors (GISTs) acquire resistance to imatinib (IM)-based targeted therapy remains the main driving force to identify novel molecular targets that are capable to increase GISTs sensitivity to the current therapeutic regimens. Secondary resistance to IM in GISTs typically occurs due to several mechanisms that include hemi- or homo-zygous deletion of the wild-type KIT allele, overexpression of focal adhesion kinase (FAK) and insulin-like growth factor receptor I (IGF-1R) amplification, BRAF mutation, a RTK switch (loss of c-KIT and gain of c-MET/AXL), etc...
December 5, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29190880/enhancement-of-the-anti-tumor-activity-of-fgfr1-inhibition-in-squamous-cell-lung-cancer-by-targeting-downstream-signaling-involved-in-glucose-metabolism
#6
Claudia Fumarola, Daniele Cretella, Silvia La Monica, Mara A Bonelli, Roberta Alfieri, Cristina Caffarra, Federico Quaini, Denise Madeddu, Angela Falco, Andrea Cavazzoni, Graziana Digiacomo, Giulia Mazzaschi, Valentina Vivo, Elisabetta Barocelli, Marcello Tiseo, Pier Giorgio Petronini, Andrea Ardizzoni
Fibroblast Growth Factor Receptor (FGFR) signaling is a complex pathway which controls several processes, including cell proliferation, survival, migration, and metabolism. FGFR1 signaling is frequently deregulated via amplification/over-expression in NSCLC of squamous histotype (SQCLC), however its inhibition has not been successfully translated in clinical setting. We determined whether targeting downstream signaling implicated in FGFR1 effects on glucose metabolism potentiates the anti-tumor activity of FGFR1 inhibition in SQCLC...
November 3, 2017: Oncotarget
https://www.readbyqxmd.com/read/29183145/emerging-drugs-for-the-treatment-of-gastrointestinal-stromal-tumour
#7
Vineela Kasireddy, Margaret von Mehren
Tyrosine kinase inhibitors (TKIs) have transformed the treatment landscape for patients with gastrointestinal stromal tumors (GIST). Unfortunately, resistance to the currently approved TKIs poses a huge challenge, and patients are in need of additional therapeutic options. Fortunately, many novel therapeutic approaches are being tested in treatment of GIST to overcome resistance to the approved TKIs Areas Covered: We performed an extensive literature (PUBMED) search to identify emerging drugs being tested in treatment of GIST in early phase clinical trials...
November 29, 2017: Expert Opinion on Emerging Drugs
https://www.readbyqxmd.com/read/29182496/phase-ii-study-of-bgj398-in-patients-with-fgfr-altered-advanced-cholangiocarcinoma
#8
Milind Javle, Maeve Lowery, Rachna T Shroff, Karl Heinz Weiss, Christoph Springfeld, Mitesh J Borad, Ramesh K Ramanathan, Lipika Goyal, Saeed Sadeghi, Teresa Macarulla, Anthony El-Khoueiry, Robin Kate Kelley, Ivan Borbath, Su Pin Choo, Do-Youn Oh, Philip A Philip, Li-Tzong Chen, Thanyanan Reungwetwattana, Eric Van Cutsem, Kun-Huei Yeh, Kristen Ciombor, Richard S Finn, Anuradha Patel, Suman Sen, Dale Porter, Randi Isaacs, Andrew X Zhu, Ghassan K Abou-Alfa, Tanios Bekaii-Saab
Purpose No standard treatment exists for patients with cholangiocarcinoma for whom first-line gemcitabine-based therapy fails. Fibroblast growth factor receptor 2 ( FGFR2) fusions/translocations are present in 13% to 17% of intrahepatic cholangiocarcinomas. BGJ398, an orally bioavailable, selective pan-FGFR kinase inhibitor, has shown preliminary clinical activity against tumors with FGFR alterations. Methods A multicenter, open-label, phase II study ( ClinicalTrials.gov identifier: NCT02150967) evaluated BGJ398 antitumor activity in patients age ≥ 18 years with advanced or metastatic cholangiocarcinoma containing FGFR2 fusions or other FGFR alterations whose disease had progressed while receiving prior therapy...
November 28, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/29177434/a-randomized-open-label-study-of-the-efficacy-and-safety-of-azd4547-monotherapy-versus-paclitaxel-for-the-treatment-of-advanced-gastric-adenocarcinoma-with-fgfr2-polysomy-or-gene-amplification
#9
E Van Cutsem, Y-J Bang, W Mansoor, R D Petty, Y Chao, D Cunningham, D R Ferry, N R Smith, P Frewer, J Ratnayake, P K Stockman, E Kilgour, D Landers
Background: Approximately 5%-10% of gastric cancers have a fibroblast growth factor receptor-2 (FGFR2) gene amplification. AZD4547 is a selective FGFR-1, 2, 3 tyrosine kinase inhibitor with potent preclinical activity in FGFR2 amplified gastric adenocarcinoma SNU16 and SGC083 xenograft models. The randomized phase II SHINE study (NCT01457846) investigated whether AZD4547 improves clinical outcome versus paclitaxel as second-line treatment in patients with advanced gastric adenocarcinoma displaying FGFR2 polysomy or gene amplification detected by fluorescence in situ hybridization...
June 1, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/29156384/targeting-fgfr-pathway-in-breast-cancer
#10
J Perez-Garcia, E Muñoz-Couselo, J Soberino, F Racca, J Cortes
Developments in breast cancer biology over the last years have permitted deconstructing the molecular profile of the most relevant breast cancer subtypes. This has led to an increase in therapeutic options, including more effective personalized therapy for breast cancer and substantial improvements in patient outcomes. Although currently there are only a few targeted therapies approved for metastatic breast cancer, the discovery of druggable kinase gene alterations has radically changed cancer treatment by providing novel and successfully actionable drug targets...
November 17, 2017: Breast: Official Journal of the European Society of Mastology
https://www.readbyqxmd.com/read/29137286/fibroblast-growth-factor-modulates-mast-cell-recruitment-in-a-murine-model-of-prostate-cancer
#11
Roberto Ronca, Roberto Tamma, Daniela Coltrini, Simona Ruggieri, Marco Presta, Domenico Ribatti
Mast cells are important modifiers of prostate tumor microenvironment. The fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) system plays a non-redundant autocrine/paracrine role in the growth, vascularization and progression of prostate tumors. Accordingly, the FGF antagonist long pentraxin-3 (PTX3) and the PTX3-derived small molecule FGF-trap NSC12 have been shown to inhibit the growth and vascularization of different FGF-dependent tumor types, including prostate cancer. In this study, we show that recombinant FGF2 is able to cause mast cell recruitment in vivo in the Matrigel plug assay...
October 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/29101463/a-drug-drug-interaction-study-to-assess-the-effect-of-the-cyp1a2-inhibitor-fluvoxamine-on-the-pharmacokinetics-of-dovitinib-tki258-in-patients-with-advanced-solid-tumors
#12
Vincent A de Weger, Sanjay Goel, Roger von Moos, Jan H M Schellens, Nicholas Mach, Eugene Tan, Suraj Anand, Jeffrey W Scott, Ulrik Lassen
PURPOSE: Dovitinib is an orally available multi tyrosine kinase inhibitor which inhibits VEGFR 1-3, FGFR 1-3, and PDGFR. This study was performed to investigate the potential drug-drug interaction of dovitinib with the CYP1A2 inhibitor fluvoxamine in patients with advanced solid tumors. METHODS: Non-smoking patients of ≥ 18 years with advanced solid tumors, excluding breast cancer, were included. Patients were treated with a dose of 300 mg in 5 days on/2 days off schedule...
November 3, 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/29071223/an-alignment-independent-3d-qsar-study-of-fgfr2-tyrosine-kinase-inhibitors
#13
Behzad Jafari, Maryam Hamzeh-Mivehroud, Ali Akbar Alizadeh, Mehdi Sharifi, Siavoush Dastmalchi
Purpose: Receptor tyrosine kinase (RTK) inhibitors are widely used pharmaceuticals in cancer therapy. Fibroblast growth factor receptors (FGFRs) are members of RTK superfamily which are highly expressed on the surface of carcinoma associate fibroblasts (CAFs). The involvement of FGFRs in different types of cancer makes them promising target in cancer therapy and hence, the identification of novel FGFR inhibitors is of great interest. In the current study we aimed to develop an alignment independent three dimensional quantitative structure-activity relationship (3D-QSAR) model for a set of 26 FGFR2 kinase inhibitors allowing the prediction of activity and identification of important structural features for these inhibitors...
September 2017: Advanced Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/29061644/comprehensive-pharmacogenomic-profiling-of-malignant-pleural-mesothelioma-identifies-a-subgroup-sensitive-to-fgfr-inhibition
#14
Josine M Quispel-Janssen, Jitendra Badhai, Laurel Schunselaar, Stacey Price, Jonathan S Brammeld, Francesco Iorio, Krishna K Kolluri, Mathew J Garnett, Anton Berns, Paul Baas, Ultan McDermott, Jacques Neefjes, Constantine Alifrangis
PURPOSE: Despite intense research, treatment options for patients with mesothelioma are limited and offer only modest survival advantage. We screened a large panel of compounds in multiple mesothelioma models, and correlated sensitivity with a range of molecular features to detect biomarkers of drug response. EXPERIMENTAL DESIGN: We utilised a high-throughput chemical inhibitor screen in a panel of 889 cancer cell lines, including both immortalised and primary early passage mesothelioma lines, alongside comprehensive molecular characterisation using Illumina whole exome sequencing, copy number analysis and Affymetrix array whole transcriptome profiling...
October 23, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29048661/combination-of-fgfr4-inhibitor-blu9931-and-5-fluorouracil-effects-on-the-biological-characteristics-of-colorectal-cancer-cells
#15
Dongbao Jiang, Jingjing Li, Jie Li, Min Wang, Chao Han, Xinru Wang, Chunlin Zhao, Yanwei Ye
The aim of this study was to explore the effects of single agent treatments and combination of Blu9931 and 5-fluorouracil (5-FU) on the biological characteristics of colorectal cancer cells and its mechanism. Blu9931 is the first selective small molecule inhibitor of the fibroblast growth factor receptor 4 (FGFR4) and exquisitely selective for FGFR4 versus other FGFR family members and all other kinases. The colorectal cancer cells HCT116 and SW620 with high expression of FGFR4 were selected for a series of functional tests including cell viability, cell proliferation, apoptosis and cell cycle detection...
October 2, 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/29040558/constitutively-active-fgfr3-disrupts-primary-cilium-length-and-ift20-trafficking-in-various-chondrocyte-models-of-achondroplasia
#16
Ludovic Martin, Nabil Kaci, Valentin Estibals, Nicolas Goudin, Meriem Garfa-Traore, Catherine Benoist-Lasselin, Emilie Dambroise, Laurence Legeai-Mallet
FGFR3 (fibroblast growth factor receptor 3) gain-of-function mutations cause dwarfisms, including achondroplasia (ACH) and thanatophoric dysplasia (TD). The constitutive activation of FGFR3 disrupts the normal process of skeletal growth. Bone-growth anomalies have been identified in skeletal ciliopathies, in which primary cilia (PC) function is disrupted. In human ACH and TD, the impact of FGFR3 mutations on PC in growth plate cartilage remains unknown. Here we showed that in chondrocytes from human (ACH, TD) and mouse Fgfr3Y367C/+ cartilage, the constitutively-active FGFR3 perturbed PC length and the sorting and trafficking of IFT20 to the PC...
October 4, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/29017058/androgen-receptor-pathway-independent-prostate-cancer-is-sustained-through-fgf-signaling
#17
Eric G Bluemn, Ilsa M Coleman, Jared M Lucas, Roger T Coleman, Susana Hernandez-Lopez, Robin Tharakan, Daniella Bianchi-Frias, Ruth F Dumpit, Arja Kaipainen, Alexandra N Corella, Yu Chi Yang, Michael D Nyquist, Elahe Mostaghel, Andrew C Hsieh, Xiaotun Zhang, Eva Corey, Lisha G Brown, Holly M Nguyen, Kenneth Pienta, Michael Ittmann, Michael Schweizer, Lawrence D True, David Wise, Paul S Rennie, Robert L Vessella, Colm Morrissey, Peter S Nelson
Androgen receptor (AR) signaling is a distinctive feature of prostate carcinoma (PC) and represents the major therapeutic target for treating metastatic prostate cancer (mPC). Though highly effective, AR antagonism can produce tumors that bypass a functional requirement for AR, often through neuroendocrine (NE) transdifferentiation. Through the molecular assessment of mPCs over two decades, we find a phenotypic shift has occurred in mPC with the emergence of an AR-null NE-null phenotype. These "double-negative" PCs are notable for elevated FGF and MAPK pathway activity, which can bypass AR dependence...
October 9, 2017: Cancer Cell
https://www.readbyqxmd.com/read/29016732/regulation-of-vascular-smooth-muscle-cell-calcification-by-syndecan-4-fgf-2-pkc%C3%AE-signalling-and-cross-talk-with-tgf%C3%AE
#18
Samantha J Borland, Thomas G Morris, Shona C Borland, Mark R Morgan, Sheila E Francis, Catherine L R Merry, Ann E Canfield
Aims: Vascular calcification is a major cause of morbidity and mortality. Fibroblast growth factor-2 (FGF-2) plays an instructive role in osteogenesis and bone development, but its role in vascular calcification was unknown. Therefore, we investigated the involvement of FGF-2 in vascular calcification and determined the mechanism by which it regulates this process. Methods and results: We demonstrate that FGF-2 expression is increased in vascular smooth muscle cells (VSMCs) induced to deposit a mineralized matrix by incubation with β-glycerophosphate...
November 1, 2017: Cardiovascular Research
https://www.readbyqxmd.com/read/28980322/fibroblast-growth-factor-21-attenuates-calcification-of-vascular-smooth-muscle-cells-in%C3%A2-vitro
#19
Fangying Cao, Shaoping Wang, Xiangrong Cao, Xiaoxiao Liu, Kun Fu, Peng Hao, Jinghua Liu
OBJECTIVES: Vascular calcification is a dysfunction of the vasculature. Recent findings indicate that fibroblast growth factor21 (FGF21), a protector of the cardiovascular system, is related to the mineral deposition of bone and enhances the osteogenic activity of bone morphogenic protein (BMP)-2. In this study, we explored whether FGF21 suppresses vascular calcification. METHODS: A calcifying model was established by culturing primary rat vascular aortic smooth muscle cells (VSMCs) in a beta-glycerophosphate (BGP)-containing calcifying medium for 14 days...
October 4, 2017: Journal of Pharmacy and Pharmacology
https://www.readbyqxmd.com/read/28978722/acquired-resistance-to-fgfr-inhibitor-in-diffuse-type-gastric-cancer-through-an-akt-independent-pkc-mediated-phosphorylation-of-gsk3%C3%AE
#20
Wen Min Lau, Eileen Teng, Kie Kyon Huang, Jin Wei Tan, Kakoli Das, Zhijiang Zang, Tania Chia, Ming Teh, Koji Kono, Wei Peng Yong, Asim Shabbir, Amy Tay, Niam Sin Phua, Patrick Tan, Shing Leng Chan, Jimmy Bok Yan So
Preclinical models of diffuse type gastric cancer (DGC) that reliably predict clinical activity of novel compounds are lacking. To overcome the problem of poor tumor cellularity in DGC, we used cells from malignant ascites to establish diffuse type gastric cancer patient-derived xenograft (PDX) models that recapitulate the primary cancer. Cells in PDX model GAGA6 with FGFR2 amplification were sensitive to AZD4547, a potent FGFR inhibitor that is being clinically evaluated for FGFR-aberrant cancer types. Intermittent in vivo treatment of GAGA6 tumors with AZD4547 gave rise to PDX tumors with acquired resistance to AZD4547, GAGA6-R...
October 4, 2017: Molecular Cancer Therapeutics
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