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https://www.readbyqxmd.com/read/28092370/api5-confers-cancer-stem-cell-like-properties-through-the-fgf2-nanog-axis
#1
K-H Song, H Cho, S Kim, H-J Lee, S J Oh, S R Woo, S-O Hong, H S Jang, K H Noh, C H Choi, J-Y Chung, S M Hewitt, J-H Kim, M Son, S-H Kim, B I Lee, H-C Park, Y-K Bae, T W Kim
Immune selection drives the evolution of tumor cells toward an immune-resistant and cancer stem cell (CSC)-like phenotype. We reported that apoptosis inhibitor-5 (API5) acts as an immune escape factor, which has a significant role in controlling immune resistance to antigen-specific T cells, but its functional association with CSC-like properties remains largely unknown. In this study, we demonstrated for the first time that API5 confers CSC-like properties, including NANOG expression, the frequency of CD44-positive cells and sphere-forming capacity...
January 16, 2017: Oncogenesis
https://www.readbyqxmd.com/read/28070720/safety-tolerability-and-pharmacokinetics-of-the-fibroblast-growth-factor-receptor-inhibitor-azd4547-in-japanese-patients-with-advanced-solid-tumours-a-phase-i-study
#2
Hideo Saka, Chiyoe Kitagawa, Yoshihito Kogure, Yasuo Takahashi, Koshi Fujikawa, Tamotsu Sagawa, Satoru Iwasa, Naoki Takahashi, Taro Fukao, Catherine Tchinou, Dónal Landers, Yasuhide Yamada
Background AZD4547 is a potent, oral, highly selective fibroblast growth factor receptor (FGFR) inhibitor in clinical development for treating tumours with a range of FGFR aberrations, including FGFR mutations, amplifications and fusions. Methods This open-label, Phase I, multicentre study (NCT01213160) evaluated the safety, pharmacokinetics, and preliminary antitumour efficacy (RECIST v1.1) of AZD4547 monotherapy in Japanese patients with advanced solid tumours. Part A was a dose-escalation part; Part B was a dose-expansion part in patients with FGFR-amplified tumours, confirmed by fluorescence in situ hybridization...
January 10, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28034880/polyclonal-secondary-fgfr2-mutations-drive-acquired-resistance-to-fgfr-inhibition-in-patients-with-fgfr2-fusion-positive-cholangiocarcinoma
#3
Lipika Goyal, Supriya K Saha, Leah Y Liu, Giulia Siravegna, Ignaty Leshchiner, Leanne G Ahronian, Jochen K Lennerz, Phuong Vu, Vikram Deshpande, Avinash Kambadakone, Benedetta Mussolin, Stephanie Reyes, Laura Henderson, Jiaoyuan Elisabeth Sun, Emily E Van Seventer, Joseph M Gurski, Sabrina Baltschukat, Barbara Schacher-Engstler, Louise Barys, Christelle Stamm, Pascal Furet, David P Ryan, James R Stone, A John Iafrate, Gad Getz, Diana Graus Porta, Ralph Tiedt, Alberto Bardelli, Dejan Juric, Ryan B Corcoran, Nabeel Bardeesy, Andrew X Zhu
Genetic alterations in the fibroblast growth factor receptor (FGFR) pathway are promising therapeutic targets in many cancers, including intrahepatic cholangiocarcinoma (ICC). The FGFR inhibitor BGJ398 displayed encouraging efficacy in patients with FGFR2 fusion-positive ICC in a phase II trial, but the durability of response was limited in some patients. Here, we report the molecular basis for acquired resistance to BGJ398 in three patients via integrative genomic characterization of cell-free circulating tumor DNA (cfDNA), primary tumors, and metastases...
December 29, 2016: Cancer Discovery
https://www.readbyqxmd.com/read/28030802/inhibition-of-the-fibroblast-growth-factor-receptor-fgfr-pathway-the-current-landscape-and-barriers-to-clinical-application
#4
REVIEW
Young Kwang Chae, Keerthi Ranganath, Peter S Hammerman, Christos Vaklavas, Nisha Mohindra, Aparna Kalyan, Maria Matsangou, Ricardo Costa, Benedito Carneiro, Victoria M Villaflor, Massimo Cristofanilli, Francis J Giles
The fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) is a tyrosine kinase signaling pathway that has a fundamental role in many biologic processes including embryonic development, tissue regeneration, and angiogenesis. Increasing evidence indicates that this pathway plays a critical role in oncogenesis via gene amplification, activating mutations, or translocation in tumors of various histologies. With multiplex sequencing technology, the detection of FGFR aberrations has become more common and is tied to cancer cell proliferation, resistance to anticancer therapies, and neoangiogenesis...
December 22, 2016: Oncotarget
https://www.readbyqxmd.com/read/28008155/combination-treatment-of-prostate-cancer-with-fgf-receptor-and-akt-kinase-inhibitors
#5
Shu Feng, Longjiang Shao, Patricia Castro, Ilsa Coleman, Peter S Nelson, Paul D Smith, Barry R Davies, Michael Ittmann
Activation of the PI3K/AKT pathway occurs in the vast majority of advanced prostate cancers (PCas). Activation of fibroblast growth factor receptor (FGFR) signaling occurs in a wide variety of malignancies, including PCa. RNA-Seq of castration resistant PCa revealed expression of multiple FGFR signaling components compatible with FGFR signaling in all cases, with multiple FGF ligands expressed in 90% of cases. Immunohistochemistry confirmed FGFR signaling in the majority of xenografts and advanced PCas. AZD5363, an AKT kinase inhibitor and AZD4547, a FGFR kinase inhibitor are under active clinical development...
December 20, 2016: Oncotarget
https://www.readbyqxmd.com/read/27998968/drug-sensitive-fgfr3-mutations-in-lung-adenocarcinoma
#6
P Chandrani, K Prabhash, A Choughule, R Prasad, V Sethunath, M Ranjan, P Iyer, J Aich, H Dhamne, D N Iyer, P Upadhyay, B Mohanty, P Chandna, R Kumar, A Joshi, V Noronha, V Patil, A Ramaswamy, A Karpe, R Thorat, P Chaudhari, A Ingle, A Dutt
BACKGROUND: Lung cancer is the leading cause of cancer-related deaths across the world. In this study we present therapeutically relevant genetic alterations in lung adenocarcinoma of Indian origin. MATERIALS AND METHODS: Forty-five primary lung adenocarcinoma tumors were sequenced for 676 amplicons using RainDance cancer panel at an average coverage of 1500X (reads per million mapped reads). To validate the findings, 49 mutations across 23 genes were genotyped in an additional set of 363 primary lung adenocarcinoma tumors using mass spectrometry...
December 19, 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/27992319/therapeutics-targeting-fgf-signaling-network-in-human-diseases
#7
REVIEW
Masaru Katoh
Fibroblast growth factor (FGF) signaling through its receptors, FGFR1, FGFR2, FGFR3, or FGFR4, regulates cell fate, angiogenesis, immunity, and metabolism. Dysregulated FGF signaling causes human diseases, such as breast cancer, chondrodysplasia, gastric cancer, lung cancer, and X-linked hypophosphatemic rickets. Recombinant FGFs are pro-FGF signaling therapeutics for tissue and/or wound repair, whereas FGF analogs and gene therapy are under development for the treatment of cardiovascular disease, diabetes, and osteoarthritis...
December 2016: Trends in Pharmacological Sciences
https://www.readbyqxmd.com/read/27988457/in-vitro-and-in-vivo-activity-of-lucitanib-in-fgfr1-2-amplified-or-mutated-cancer-models
#8
Federica Guffanti, Rosaria Chilà, Ezia Bello, Massimo Zucchetti, Monique Zangarini, Laura Ceriani, Mariella Ferrari, Monica Lupi, Anne Jacquet-Bescond, Mike F Burbridge, Marie-Jeanne Pierrat, Giovanna Damia
The fibroblast growth factor receptor (FGFR) pathway has been implicated both as an escape mechanism from anti-angiogenic therapy and as a driver oncogene in different tumor types. Lucitanib is a small molecule inhibitor of vascular endothelial growth factor (VEGF) receptors 1 to 3 (VEGFR1 to 3), platelet derived growth factor α/β (PDGFRα/β) and FGFR1-3 tyrosine kinases and has demonstrated activity in a phase I/II clinical study, with objective RECIST responses in breast cancer patients with FGFR1 or FGF3/4/19 gene amplification, as well as in patients anticipated to benefit from anti-angiogenic agents...
December 15, 2016: Neoplasia: An International Journal for Oncology Research
https://www.readbyqxmd.com/read/27988109/receptor-tyrosine-kinases-translocation-partners-in-hematopoietic-disorders
#9
REVIEW
Katelyn N Nelson, Malalage N Peiris, April N Meyer, Asma Siari, Daniel J Donoghue
Receptor tyrosine kinases (RTKs) activate various signaling pathways and regulate cellular proliferation, survival, migration, and angiogenesis. Malignant neoplasms often circumvent or subjugate these pathways by promoting RTK overactivation through mutation or chromosomal translocation. RTK translocations create a fusion protein containing a dimerizing partner fused to an RTK kinase domain, resulting in constitutive kinase domain activation, altered RTK cellular localization, upregulation of downstream signaling, and novel pathway activation...
January 2017: Trends in Molecular Medicine
https://www.readbyqxmd.com/read/27940520/exploring-the-benefit-risk-associated-with-antiangiogenic-agents-for-the-treatment-of-non-small-cell-lung-cancer-patients
#10
Razelle Kurzrock, David J Stewart
Following the approval of bevacizumab, an antibody targeting vascular endothelial growth factor-A (VEGF-A), for advanced non-squamous non-small cell lung cancer (NSCLC) in 2006, intensive efforts were put into the clinical development of antiangiogenic agents for NSCLC. Currently, the other antiangiogenic agents approved for NSCLC are ramucirumab, a VEGF receptor-2 (VEGFR-2)-targeting antibody indicated for both squamous and non-squamous NSCLC in the United States, and nintedanib, an anti-VEGFR-½/3, platelet-derived growth factor receptor (PDGFR)-α/β, fibroblast growth factor receptor (FGFR)-½/3 angiokinase inhibitor indicated for adenocarcinoma of the lung in the European Union...
December 9, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27940440/the-fgfr-inhibitor-bgj398-has-activity-in-tumors-with-fgfr-alterations
#11
(no author information available yet)
BGJ398 has a tolerable safety profile at the determined dose and activity against several tumor types.
January 2017: Cancer Discovery
https://www.readbyqxmd.com/read/27933954/discovery-of-5-amino-1-2-methyl-3h-benzimidazol-5-yl-pyrazol-4-yl-1h-indol-2-yl-methanone-ch5183284-debio-1347-an-orally-available-and-selective-fibroblast-growth-factor-receptor-fgfr-inhibitor
#12
Hirosato Ebiike, Naoki Taka, Masayuki Matsushita, Masayuki Ohmori, Kyoko Takami, Ikumi Hyohdoh, Masami Kohchi, Tadakatsu Hayase, Hiroki Nishii, Kenji Morikami, Yoshito Nakanishi, Nukinori Akiyama, Hidetoshi Shindoh, Nobuya Ishii, Takehito Isobe, Hiroharu Matsuoka
The fibroblast growth factor receptor (FGFR) family of receptor tyrosine kinases regulates multiple biological processes, such as cell proliferation, migration, apoptosis, and differentiation. Various genetic alterations that drive activation of the receptors and the pathway are associated with tumor growth and survival; therefore, the FGFR family represents an attractive therapeutic target for treating cancer. Here, we report the discovery and the pharmacological profiles of 8 (CH5183284/Debio 1347), an orally available and selective inhibitor of FGFR1, FGFR2, and FGFR3...
December 8, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27930669/development-of-rna-fish-assay-for-detection-of-oncogenic-fgfr3-tacc3-fusion-genes-in-ffpe-samples
#13
Masahiro Kurobe, Takahiro Kojima, Kouichi Nishimura, Shuya Kandori, Takashi Kawahara, Takayuki Yoshino, Satoshi Ueno, Yuichi Iizumi, Koji Mitsuzuka, Yoichi Arai, Hiroshi Tsuruta, Tomonori Habuchi, Takashi Kobayashi, Yoshiyuki Matsui, Osamu Ogawa, Mikio Sugimoto, Yoshiyuki Kakehi, Yoshiyuki Nagumo, Masakazu Tsutsumi, Takehiro Oikawa, Koji Kikuchi, Hiroyuki Nishiyama
INTRODUCTION AND OBJECTIVES: Oncogenic FGFR3-TACC3 fusions and FGFR3 mutations are target candidates for small molecule inhibitors in bladder cancer (BC). Because FGFR3 and TACC3 genes are located very closely on chromosome 4p16.3, detection of the fusion by DNA-FISH (fluorescent in situ hybridization) is not a feasible option. In this study, we developed a novel RNA-FISH assay using branched DNA probe to detect FGFR3-TACC3 fusions in formaldehyde-fixed paraffin-embedded (FFPE) human BC samples...
2016: PloS One
https://www.readbyqxmd.com/read/27914362/an-overview-of-the-binding-models-of-fgfr-tyrosine-kinases-in-complex-with-small-molecule-inhibitors
#14
REVIEW
Weiyan Cheng, Mixiang Wang, Xin Tian, Xiaojian Zhang
The fibroblast growth factor receptor (FGFR) family receptor tyrosine kinase (RTK) includes four structurally related members, termed as FGFR1, FGFR2, FGFR3, and FGFR4. Given its intimate role in the progression of several solid tumors, excessive FGFR signaling provides an opportunity for anticancer therapy. Along with extensive pharmacological studies validating the therapeutic potential of targeting the FGFRs for cancer treatment, co-crystal structures of FGFRs/inhibitors are continuously coming up to study the mechanism of actions and explore new inhibitors...
November 25, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27885740/asp5878-a-selective-fgfr-inhibitor-to-treat-fgfr3-dependent-urothelial-cancer-with-or-without-chemoresistance
#15
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/27883224/basic-fibroblast-growth-factor-regulates-rex1-expression-via-il-6-in-stem-cells-isolated-from-human-exfoliated-deciduous-teeth
#16
Nunthawan Nowwarote, Waleerat Sukarawan, Prasit Pavasant, Thanaphum Osathanon
Basic fibroblast growth factor (bFGF) regulates pluripotent marker expression and cellular differentiation in various cell types. However, the mechanism by which bFGF regulates REX1 expression in stem cells, isolated from human exfoliated deciduous teeth (SHEDs) remains unclear. The aim of the present study was to investigate the regulation of REX1 expression by bFGF in SHEDs. SHEDs were isolated and characterized. Their mRNA and protein expression levels were determined using real-time polymerase chain reaction and enzyme-linked immunosorbent assay, respectively...
November 24, 2016: Journal of Cellular Biochemistry
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
#17
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...
January 10, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/27852792/fgfr-tacc-gene-fusions-in-human-glioma
#18
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/27837149/chronic-hyperphosphatemia-and-vascular-calcification-are-reduced-by-stable-delivery-of-soluble-klotho
#19
Julia M Hum, Linda M O'Bryan, Arun K Tatiparthi, Taryn A Cass, Erica L Clinkenbeard, Martin S Cramer, Manoj Bhaskaran, Robert L Johnson, Jonathan M Wilson, Rosamund C Smith, Kenneth E White
αKlotho (αKL) regulates mineral metabolism, and diseases associated with αKL deficiency are characterized by hyperphosphatemia and vascular calcification (VC). αKL is expressed as a membrane-bound protein (mKL) and recognized as the coreceptor for fibroblast growth factor-23 (FGF23) and a circulating soluble form (cKL) created by endoproteolytic cleavage of mKL. The functions of cKL with regard to phosphate metabolism are unclear. We tested the ability of cKL to regulate pathways and phenotypes associated with hyperphosphatemia in a mouse model of CKD-mineral bone disorder and αKL-null mice...
November 11, 2016: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/27837028/asp5878-a-novel-inhibitor-of-fgfr1-2-3-and-4-inhibits-the-growth-of-fgf19-expressing-hepatocellular-carcinoma
#20
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...
January 2017: Molecular Cancer Therapeutics
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