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BGJ398

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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
#1
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
#2
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
#3
Leisl Packer, Xinyan Geng, Vanessa F Bonazzi, Robert Ju, Clare Mahon, Margaret C Cummings, Sally-Anne Stephenson, Pamela M Pollock
Improved therapeutic approaches are needed for the treatment of recurrent and metastatic endometrial cancer (EC). ECs display hyper-activation of the MAPK and PI3K pathways, the result of somatic aberrations in genes such as FGFR2, KRAS, PTEN, PIK3CA and PIK3R1. FGFR2, as well as the PI3K pathway, have emerged as potential therapeutic targets in EC. Activation of the PI3K pathway is seen in >90% of FGFR2mutant ECs. 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...
January 23, 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
#4
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
#5
(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
#6
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
#7
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
#8
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...
August 16, 2016: Journal of Neuro-oncology
https://www.readbyqxmd.com/read/27409346/preclinical-evaluation-of-potential-therapeutic-targets-in-dedifferentiated-liposarcoma
#9
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
#10
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
#11
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
#12
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
https://www.readbyqxmd.com/read/27245147/fgfr-inhibitors-effects-on-cancer-cells-tumor-microenvironment-and-whole-body-homeostasis-review
#13
REVIEW
Masaru Katoh
Fibroblast growth factor (FGF)2, FGF4, FGF7 and FGF20 are representative paracrine FGFs binding to heparan-sulfate proteoglycan and fibroblast growth factor receptors (FGFRs), whereas FGF19, FGF21 and FGF23 are endocrine FGFs binding to Klotho and FGFRs. FGFR1 is relatively frequently amplified and overexpressed in breast and lung cancer, and FGFR2 in gastric cancer. BCR-FGFR1, CNTRL-FGFR1, CUX1-FGFR1, FGFR1OP-FGFR1, MYO18A-FGFR1 and ZMYM2-FGFR1 fusions in myeloproliferative neoplasms are non-receptor-type FGFR kinases, whereas FGFR1-TACC1, FGFR2-AFF3, FGFR2-BICC1, FGFR2-PPHLN1, FGFR3-BAIAP2L1 and FGFR3-TACC3 fusions in solid tumors are transmembrane-type FGFRs with C-terminal alterations...
July 2016: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/27216979/antitumor-effect-of-fgfr-inhibitors-on-a-novel-cholangiocarcinoma-patient-derived-xenograft-mouse-model-endogenously-expressing-an-fgfr2-ccdc6-fusion-protein
#14
Yu Wang, Xiwei Ding, Shaoqing Wang, Catherine D Moser, Hassan M Shaleh, Essa A Mohamed, Roongruedee Chaiteerakij, Loretta K Allotey, Gang Chen, Katsuyuki Miyabe, Melissa S McNulty, Albert Ndzengue, Emily G Barr Fritcher, Ryan A Knudson, Patricia T Greipp, Karl J Clark, Michael S Torbenson, Benjamin R Kipp, Jie Zhou, Michael T Barrett, Michael P Gustafson, Steven R Alberts, Mitesh J Borad, Lewis R Roberts
Cholangiocarcinoma is a highly lethal cancer with limited therapeutic options. Recent genomic analysis of cholangiocarcinoma has revealed the presence of fibroblast growth factor receptor 2 (FGFR2) fusion proteins in up to 13% of intrahepatic cholangiocarcinoma (iCCA). FGFR fusions have been identified as a novel oncogenic and druggable target in a number of cancers. In this study, we established a novel cholangiocarcinoma patient derived xenograft (PDX) mouse model bearing an FGFR2-CCDC6 fusion protein from a metastatic lung nodule of an iCCA patient...
September 28, 2016: Cancer Letters
https://www.readbyqxmd.com/read/27064282/tyrosine-kinase-inhibitor-nvp-bgj398-functionally-improves-fgfr3-related-dwarfism-in-mouse-model
#15
Davide Komla-Ebri, Emilie Dambroise, Ina Kramer, Catherine Benoist-Lasselin, Nabil Kaci, Cindy Le Gall, Ludovic Martin, Patricia Busca, Florent Barbault, Diana Graus-Porta, Arnold Munnich, Michaela Kneissel, Federico Di Rocco, Martin Biosse-Duplan, Laurence Legeai-Mallet
Achondroplasia (ACH) is the most frequent form of dwarfism and is caused by gain-of-function mutations in the fibroblast growth factor receptor 3-encoding (FGFR3-encoding) gene. Although potential therapeutic strategies for ACH, which aim to reduce excessive FGFR3 activation, have emerged over many years, the use of tyrosine kinase inhibitor (TKI) to counteract FGFR3 hyperactivity has yet to be evaluated. Here, we have reported that the pan-FGFR TKI, NVP-BGJ398, reduces FGFR3 phosphorylation and corrects the abnormal femoral growth plate and calvaria in organ cultures from embryos of the Fgfr3Y367C/+ mouse model of ACH...
May 2, 2016: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/27053219/evaluation-of-fgfr3-as-a-therapeutic-target-in-head-and-neck-squamous-cell-carcinoma
#16
Anne von Mässenhausen, Mario Deng, Hannah Billig, Angela Queisser, Wenzel Vogel, Glen Kristiansen, Andreas Schröck, Friedrich Bootz, Friederike Göke, Alina Franzen, Lynn Heasley, Jutta Kirfel, Johannes Brägelmann, Sven Perner
BACKGROUND: Although head and neck squamous cell carcinoma (HNSCC) is the sixth most common tumour entity worldwide, it remains a clinical challenge. Large-scale explorative genomic projects have identified several genes as potential targets for therapy, including fibroblast growth factor receptor 3 (FGFR3). AIMS: The aim of this study was to investigate the biological significance of wild-type and mutated FGFR3 to evaluate its potential as a novel therapeutic target in HNSCC...
April 7, 2016: Targeted Oncology
https://www.readbyqxmd.com/read/26762209/fgfr-inhibitor-ameliorates-hypophosphatemia-and-impaired-engrailed-1-wnt-signaling-in-fgf2-high-molecular-weight-isoform-transgenic-mice
#17
Erxia Du, Liping Xiao, Marja M Hurley
High molecular weight FGF2 transgenic (HMWTg) mouse phenocopies the Hyp mouse, homolog of human X-linked hypophosphatemic rickets with hypophosphatemis, and abnormal FGF23, FGFR, Klotho signaling in kidney. Since abnormal Wnt signaling was reported in Hyp mice we assessed whether Wnt signaling was impaired in HMWTg kidneys and the effect of blocking FGF receptor (FGFR) signaling. Bone mineral density and bone mineral content in female HMWTg mice were significantly reduced. HMWTg mice were gavaged with FGFR inhibitor NVP-BGJ398, or vehicle and were euthanized 24 h post treatment...
September 2016: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/26637881/targeting-fibroblast-growth-factor-receptor-fgfr-with-bgj398-in-a-gastric-cancer-model
#18
Katharina Schmidt, Christian Moser, Claus Hellerbrand, Derek Zieker, Christine Wagner, Julia Redekopf, Hans J Schlitt, Edward K Geissler, Sven A Lang
AIM: To assess the efficacy of targeting fibroblast growth factor receptor (FGFR) with the pan-FGFR inhibitor BGJ398 in a gastric cancer (GC) model. MATERIALS AND METHODS: Expression of FGFRs was determined in GC cell lines (KKLS, MKN-45, TMK-1). Impact of the FGFR inhibitor BGJ398 on growth, motility, signaling, expression of transcription factors and secretion of vascular endothelial growth factor-A (VEGFA) was determined in vitro. Results were validated in subcutaneous tumor models...
December 2015: Anticancer Research
https://www.readbyqxmd.com/read/26581390/upregulation-of-egfr-signaling-is-correlated-with-tumor-stroma-remodeling-and-tumor-recurrence-in-fgfr1-driven-breast-cancer
#19
Xue B Holdman, Thomas Welte, Kimal Rajapakshe, Adam Pond, Cristian Coarfa, Qianxing Mo, Shixia Huang, Susan G Hilsenbeck, Dean P Edwards, Xiang Zhang, Jeffrey M Rosen
INTRODUCTION: Despite advances in early detection and adjuvant targeted therapies, breast cancer is still the second most common cause of cancer mortality among women. Tumor recurrence is one of the major contributors to breast cancer mortality. However, the mechanisms underlying this process are not completely understood. In this study, we investigated the mechanisms of tumor dormancy and recurrence in a preclinical mouse model of breast cancer. METHODS: To elucidate the mechanisms driving tumor recurrence, we employed a transplantable Wnt1/inducible fibroblast growth factor receptor (FGFR) 1 mouse mammary tumor model and utilized an FGFR specific inhibitor, BGJ398, to study the recurrence after treatment...
November 18, 2015: Breast Cancer Research: BCR
https://www.readbyqxmd.com/read/26494904/multikinase-activity-of-fibroblast-growth-factor-receptor-fgfr-inhibitors-su5402-pd173074-azd1480-azd4547-and-bgj398-compromises-the-use-of-small-chemicals-targeting-fgfr-catalytic-activity-for-therapy-of-short-stature-syndromes
#20
Iva Gudernova, Iva Vesela, Lukas Balek, Marcela Buchtova, Hana Dosedelova, Michaela Kunova, Jakub Pivnicka, Iva Jelinkova, Lucie Roubalova, Alois Kozubik, Pavel Krejci
Activating mutations in the fibroblast growth factor receptor 3 (FGFR3) cause the most common genetic form of human dwarfism, achondroplasia (ACH). Small chemical inhibitors of FGFR tyrosine kinase activity are considered to be viable option for treating ACH, but little experimental evidence supports this claim. We evaluated five FGFR tyrosine kinase inhibitors (TKIs) (SU5402, PD173074, AZD1480, AZD4547 and BGJ398) for their activity against FGFR signaling in chondrocytes. All five TKIs strongly inhibited FGFR activation in cultured chondrocytes and limb rudiment cultures, completely relieving FGFR-mediated inhibition of chondrocyte proliferation and maturation...
January 1, 2016: Human Molecular Genetics
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