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BGJ398

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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
#1
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/28968431/breast-cancer-cell-derived-fibroblast-growth-factors-enhance-osteoclast-activity-and-contribute-to-the-formation-of-metastatic-lesions
#2
Kelly Aukes, Cynthia Forsman, Nicholas J Brady, Kristina Astleford, Nicholas Blixt, Deepali Sachdev, Eric D Jensen, Kim C Mansky, Kathryn L Schwertfeger
Fibroblast growth factors (FGFs) and their receptors (FGFRs) have been implicated in promoting breast cancer growth and progression. While the autocrine effects of FGFR activation in tumor cells have been extensively studied, little is known about the effects of tumor cell-derived FGFs on cells in the microenvironment. Because FGF signaling has been implicated in the regulation of bone formation and osteoclast differentiation, we hypothesized that tumor cell-derived FGFs are capable of modulating osteoclast function and contributing to growth of metastatic lesions in the bone...
2017: PloS One
https://www.readbyqxmd.com/read/28938491/inhibition-of-fgfr-signaling-partially-rescues-hypophosphatemic-rickets-in-hmwfgf2-tg-male-mice
#3
Liping Xiao, Erxia Du, Collin Homer-Bouthiette, Marja M Hurley
Transgenic mice harboring high molecular weight fibroblast growth factor (FGF)2 isoforms (HMWTg) in osteoblast lineage cells phenocopy human X-linked hypophosphatemic rickets (XLH) and Hyp murine model of XLH demonstrating increased FGF23/FGF receptor signaling and hypophosphatemic rickets. Because HMWFGF2 was upregulated in bones of Hyp mice and abnormal FGF receptor (FGFR) signaling is important in XLH, HMWTg mice were used to examine the effect of the FGFR inhibitor NVP-BGJ398, now in clinical trials for cancer therapy, on hypophosphatemic rickets...
October 1, 2017: Endocrinology
https://www.readbyqxmd.com/read/28901443/basic-fibroblast-growth-factor-increases-ift88-expression-in-chondrocytes
#4
Daolu Zhan, Wei Xiang, Fengjing Guo, Yuanzheng Ma
Intraflagellar transport protein 88 (IFT88) is protein crucial for the assembly and maintenance of primary cilia in chondrocytes. Primary cilia regulate mechanical and chemical signals in chondrocytes; however, the effects of cytokines on IFT88 expression and cilia formation and maintenance remain to be elucidated. Therefore, the role of basic fibroblast growth factor (bFGF) on IFT88 expression were examined in theATDC5 murine chondrocytic line, in order to investigate the signaling pathways involved in this process...
November 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28885691/fibroblast-growth-factor-2-induces-proliferation-and-distribution-of-g2-m-phase-of-bovine-endometrial-cells-involving-activation-of-pi3k-akt-and-mapk-cell-signaling-and-prevention-of-effects-of-er-stress
#5
Whasun Lim, Hyocheol Bae, Fuller W Bazer, Gwonhwa Song
Fibroblast growth factor 2 (FGF2) is abundantly expressed in conceptuses and endometria during pregnancy in diverse animal models including domestic animals. However, its intracellular mechanism of action has not been reported for bovine endometrial cells. Therefore, the aim of this study was to identify functional roles of FGF2 in bovine endometrial (BEND) cell line which has served as a good model system for investigating regulation of signal transduction following treatment with interferon-tau (IFNT) in vitro...
September 8, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28782829/the-participation-of-fibroblast-growth-factor-23-fgf23-in-the-progression-of-osteoporosis-via-jak-stat-pathway
#6
Lijun Xu, Lixia Zhang, Huijuan Zhang, Zaigang Yang, Lei Qi, Yurong Wang, Shuxin Ren
Osteoporosis (OP) is a major skeletal disorder for the old man. The fibroblast growth factor 23 (FGF23) is a phosphaturic hormone produced by osteoblasts and osteocytes. However, the regulatory mechanisms of FGF23 in the progression of osteoporosis remain poorly understood. This study aims to explore the downstream regulating pathway of FGF23 in postmenopausal osteoporosis. The rat model of osteoporosis was established through ovariectomy (OVX). The investigation demonstrated that the serum levels of FGF23 and the phosphorylation levels of JAK2, STAT1 and STAT3 were up-regulated in the OVX + NVP-BGJ398 group while were down-regulated in the OVX + Anti-FGF23 group than that in the OVX group...
August 7, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28753560/enhancement-of-the-anti-tumor-activity-of-fgfr1-inhibition-in-squamous-cell-lung-cancer-by-targeting-downstream-signaling-involved-in-glucose-metabolism
#7
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...
July 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/28646488/mutation-in-the-fgfr1-tyrosine-kinase-domain-or-inactivation-of-pten-is-associated-with-acquired-resistance-to-fgfr-inhibitors-in-fgfr1-driven-leukemia-lymphomas
#8
John K Cowell, Haiyan Qin, Tianxiang Hu, Qing Wu, Aaron Bhole, Mingqiang Ren
Stem cell leukemia/lymphoma syndrome (SCLL) is driven by constitutive activation of chimeric FGFR1 kinases generated by chromosome translocations. We have shown that FGFR inhibitors significantly suppress leukemia and lymphoma development in vivo, and cell viability in vitro. Since resistance to targeted therapies is a major reason for relapse, we developed FGFR1-overexpressing mouse and human cell lines that are resistant to the specific FGFR inhibitors AZD4547 and BGJ398, as well as non-specific inhibitors, such as ponatinib, TKI258 and E3810...
November 1, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/28350116/selective-fgfr-inhibitor-bgj398-inhibits-phosphorylation-of-akt-and-stat3-and-induces-cytotoxicity-in-sphere-cultured-ovarian-cancer-cells
#9
Hwa Jun Cha, Jung Hye Choi, In Chul Park, Chun Ho Kim, Sung Kwan An, Tae Jin Kim, Jae Ho Lee
Epithelial ovarian cancer is the most aggressive and lethal among the gynecological malignancies, which is often found disseminated to peritoneal cavity at the time of diagnosis. There is accumulating evidence on the existence of genetic alteration and amplification of fibroblast growth factor receptor (FGFR) in various cancers. Also the aberrated FGFR/FGF signaling has been implicated in cancer development and tumor microenvironment. However, the antitumor activity of BGJ398, a selective inhibitor of FGFR 1/2/3 against ovarian cancer still remains unknown...
March 15, 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/28255027/akt-activation-mediates-acquired-resistance-to-fibroblast-growth-factor-receptor-inhibitor-bgj398
#10
Jharna Datta, Senthilkumar Damodaran, Hannah Parks, Cristina Ocrainiciuc, Jharna Miya, Lianbo Yu, Elijah P Gardner, Eric Samorodnitsky, Michele R Wing, Darshna Bhatt, John Hays, Julie W Reeser, Sameek Roychowdhury
Activation of FGFR signaling through mutations, amplifications, or fusions involving FGFR1, 2, 3, or 4 is seen in multiple tumors, including lung, bladder, and cholangiocarcinoma. Currently, several clinical trials are evaluating the role of novel FGFR inhibitors in solid tumors. As we move forward with FGFR inhibitors clinically, we anticipate the emergence of resistance with treatment. Consequently, we sought to study the mechanism(s) of acquired resistance to FGFR inhibitors using annotated cancer cell lines...
April 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28119489/pi3k-inhibitors-synergize-with-fgfr-inhibitors-to-enhance-antitumor-responses-in-fgfr2-mutant-endometrial-cancers
#11
Leisl M Packer, Xinyan Geng, Vanessa F Bonazzi, Robert J Ju, Clare E Mahon, Margaret C Cummings, Sally-Anne Stephenson, Pamela M Pollock
Improved therapeutic approaches are needed for the treatment of recurrent and metastatic endometrial cancer. Endometrial cancers display hyperactivation of the MAPK and PI3K pathways, the result of somatic aberrations in genes such as FGFR2, KRAS, PTEN, PIK3CA, and PIK3R1 The FGFR2 and PI3K pathways, have emerged as potential therapeutic targets in endometrial cancer. Activation of the PI3K pathway is seen in more than 90% of FGFR2(mutant) endometrial cancers. This study aimed to examine the efficacy of the pan-FGFR inhibitor BGJ398 with pan-PI3K inhibitors (GDC-0941, BKM120) and the p110α-selective inhibitor BYL719...
April 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28034880/polyclonal-secondary-fgfr2-mutations-drive-acquired-resistance-to-fgfr-inhibition-in-patients-with-fgfr2-fusion-positive-cholangiocarcinoma
#12
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...
March 2017: Cancer Discovery
https://www.readbyqxmd.com/read/27940440/the-fgfr-inhibitor-bgj398-has-activity-in-tumors-with-fgfr-alterations
#13
(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/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
#14
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/27535980/targeting-fibroblast-growth-factor-receptor-1-for-treatment-of-soft-tissue-sarcoma
#15
Priya Chudasama, Marcus Renner, Melanie Straub, Sadaf S Mughal, Barbara Hutter, Zeynep Kosaloglu, Ron Schweßinger, Matthias Scheffler, Ingo Alldinger, Simon Schimmack, Thorsten Persigehl, Carsten Kobe, Dirk Jäger, Christof von Kalle, Peter Schirmacher, Marie-Kristin Beckhaus, Stephan Wolf, Christoph Heining, Stefan Gröschel, Jürgen Wolf, Benedikt Brors, Wilko Weichert, Hanno Glimm, Claudia Scholl, Gunhild Mechtersheimer, Katja Specht, Stefan Fröhling
PURPOSE: Altered FGFR1 signaling has emerged as a therapeutic target in epithelial malignancies. In contrast, the role of FGFR1 in soft-tissue sarcoma (STS) has not been established. Prompted by the detection and subsequent therapeutic inhibition of amplified FGFR1 in a patient with metastatic leiomyosarcoma, we investigated the oncogenic properties of FGFR1 and its potential as a drug target in patients with STS. EXPERIMENTAL DESIGN: The frequency of FGFR1 amplification and overexpression, as assessed by FISH, microarray-based comparative genomic hybridization and mRNA expression profiling, SNP array profiling, and RNA sequencing, was determined in three patient cohorts...
August 17, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27531351/clinical-utility-and-treatment-outcome-of-comprehensive-genomic-profiling-in-high-grade-glioma-patients
#16
Deborah T Blumenthal, Addie Dvir, Alexander Lossos, Tzahala Tzuk-Shina, Tzach Lior, Dror Limon, Shlomit Yust-Katz, Alejandro Lokiec, Zvi Ram, Jeffrey S Ross, Siraj M Ali, Roi Yair, Lior Soussan-Gutman, Felix Bokstein
Genomic research of high grade glioma (HGG) has revealed complex biology with potential for therapeutic impact. However, the utilization of this information and impact upon patient outcome has yet to be assessed. We performed capture-based next generation sequencing (NGS) genomic analysis assay of 236/315 cancer-associated genes, with average depth of over 1000 fold, to guide treatment in HGG patients. We reviewed clinical utility and response rates in correlation to NGS results. Forty-three patients were profiled: 34 glioblastomas, 8 anaplastic astrocytomas, and one patient with anaplastic oligodendroglioma...
October 2016: Journal of Neuro-oncology
https://www.readbyqxmd.com/read/27409346/preclinical-evaluation-of-potential-therapeutic-targets-in-dedifferentiated-liposarcoma
#17
Robert Hanes, Iwona Grad, Susanne Lorenz, Eva W Stratford, Else Munthe, Chilamakuri Chandra Sekhar Reddy, Leonardo A Meza-Zepeda, Ola Myklebost
Sarcomas are rare cancers with limited treatment options. Patients are generally treated by chemotherapy and/or radiotherapy in combination with surgery, and would benefit from new personalized approaches. In this study we demonstrate the potential of combining personal genomic characterization of patient tumors to identify targetable mutations with in vitro testing of specific drugs in patient-derived cell lines. We have analyzed three metastases from a patient with high-grade metastatic dedifferentiated liposarcoma (DDLPS) by exome and transcriptome sequencing as well as DNA copy number analysis...
August 23, 2016: Oncotarget
https://www.readbyqxmd.com/read/27406998/inhibition-of-fgf-signalling-pathway-augments-the-expression-of-pluripotency-and-trophoblast-lineage-marker-genes-in-porcine-parthenogenetic-blastocyst
#18
L Y Li, M M Li, S F Yang, J Zhang, Z Li, H Zhang, L Zhu, X Zhu, V Verma, Q Liu, D Shi, B Huang
The consistent failure to isolate bona fide pluripotent cell lines from livestock indicates that the underlying mechanisms of early lineage specification are poorly defined. Unlike other species, the contrivances of segregation have been comprehensively studied in the mouse. In mouse, FGF/MAPK signalling pathway dictates the segregation of hypoblast (primitive endoderm). However, it is not evident whether this mechanism is also conserved in livestock. Here, in this study, we examined the roles of FGF/MAP kinase signalling pathways in porcine parthenogenetic embryos during the early development...
October 2016: Reproduction in Domestic Animals, Zuchthygiene
https://www.readbyqxmd.com/read/27391347/sclltargeting-fgfr1-to-suppress-leukemogenesis-in-syndromic-and-de-novo-aml-in-murine-models
#19
Qing Wu, Aaron Bhole, Haiyan Qin, Judith Karp, Sami Malek, John K Cowell, Mingqiang Ren
Although over expression of chimeric FGFR1 kinase consistently leads to the development of AML in the rare Stem Cell Leukemia and Lymphoma syndrome, we now show that overexpression of FGFR1 is also seen in up to 20% of non-syndromic, de novo AML. To determine whether targeting FGFR1 in both of these AML subtypes can suppress leukemogenesis, we evaluated the effects of different FGFR1 inhibitors in a side-by-side comparison for their ability to affect in vitro proliferation in FGFR1 overexpressing murine and human cells lines...
August 2, 2016: Oncotarget
https://www.readbyqxmd.com/read/27260401/meckel-s-and-condylar-cartilages-anomalies-in-achondroplasia-result-in-defective-development-and-growth-of-the-mandible
#20
Martin Biosse Duplan, Davide Komla-Ebri, Yann Heuzé, Valentin Estibals, Emilie Gaudas, Nabil Kaci, Catherine Benoist-Lasselin, Michel Zerah, Ina Kramer, Michaela Kneissel, Diana Grauss Porta, Federico Di Rocco, Laurence Legeai-Mallet
Activating FGFR3 mutations in human result in achondroplasia (ACH), the most frequent form of dwarfism, where cartilages are severely disturbed causing long bones, cranial base and vertebrae defects. Because mandibular development and growth rely on cartilages that guide or directly participate to the ossification process, we investigated the impact of FGFR3 mutations on mandibular shape, size and position. By using CT scan imaging of ACH children and by analyzing Fgfr3(Y367C/+) mice, a model of ACH, we show that FGFR3 gain-of-function mutations lead to structural anomalies of primary (Meckel's) and secondary (condylar) cartilages of the mandible, resulting in mandibular hypoplasia and dysmorphogenesis...
July 15, 2016: Human Molecular Genetics
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