scholarly journals Therapeutic Targeting of Fibroblast Growth Factor Receptors in Gastric Cancer

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Mikito Inokuchi ◽  
Yoshitaka Fujimori ◽  
Sho Otsuki ◽  
Yuya Sato ◽  
Masatoshi Nakagawa ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Growth Factor ◽  
Tyrosine Kinase ◽  
Signaling Pathways ◽  
Fibroblast Growth Factor ◽  
Growth Factor Receptor ◽  
Growth Factor Receptors ◽  
Fibroblast Growth ◽  
Fibroblast Growth Factor Receptors ◽  
Genomic Amplification

Chemotherapy has become the global standard treatment for patients with metastatic or unresectable gastric cancer (GC), although outcomes remain unfavorable. Many molecular-targeted therapies inhibiting signaling pathways of various tyrosine kinase receptors have been developed, and monoclonal antibodies targeting human epidermal growth factor receptor 2 (HER2) have become standard therapy for HER2-positive GC. An inhibitor of vascular endothelial growth factor receptor 2 or MET has also produced promising results in patients with GC. Fibroblast growth factor receptors (FGFR) play key roles in tumor growth via activated signaling pathways in GC. Genomic amplification of FGFR2 leads to the aberrant activation found in GC tumors and is related to survival in patients with GC. This review discusses the clinical relevance of FGFR in GC and examines FGFR as a potential therapeutic target in patients with GC. Preclinical studies in animal models suggest that multitargeted tyrosine kinase inhibitors (TKIs), including FGFR inhibitor, suppress tumor cell proliferation and delay tumor progression. Several TKIs are now being evaluated in clinical trials as treatment for metastatic or unresectable GC harboring FGFR2 amplification.

Up-regulation and co-expression of fibroblast growth factor receptors in human gastric cancer

2000 ◽  
Vol 126 (9) ◽  
pp. 519-528 ◽  
Author(s):  
Eun-Young Shin ◽  
Bin-Ho Lee ◽  
Jong-Ho Yang ◽  
Kyeong-Sun Shin ◽  
Geon-Kook Lee ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Growth Factor Receptors ◽  
Human Gastric Cancer ◽  
Fibroblast Growth ◽  
Fibroblast Growth Factor Receptors

scholarly journals Fibroblast growth factor receptors in breast cancer

Tumor Biology ◽  
2017 ◽  
Vol 39 (5) ◽  
pp. 101042831769837 ◽  
Author(s):  
Shuwei Wang ◽  
Zhongyang Ding
Keyword(s):  
Breast Cancer ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Tyrosine Kinases ◽  
Growth Factor Receptor ◽  
Growth Factor Receptors ◽  
Fibroblast Growth ◽  
Fibroblast Growth Factor Receptors ◽  
Genetic Studies ◽  
The Common

Fibroblast growth factor receptors are growth factor receptor tyrosine kinases, exerting their roles in embryogenesis, tissue homeostasis, and development of breast cancer. Recent genetic studies have identified some subtypes of fibroblast growth factor receptors as strong genetic loci associated with breast cancer. In this article, we review the recent epidemiological findings and experiment results of fibroblast growth factor receptors in breast cancer. First, we summarized the structure and physiological function of fibroblast growth factor receptors in humans. Then, we discussed the common genetic variations in fibroblast growth factor receptors that affect breast cancer risk. In addition, we also introduced the potential roles of each fibroblast growth factor receptors isoform in breast cancer. Finally, we explored the potential therapeutics targeting fibroblast growth factor receptors for breast cancer. Based on the biological mechanisms of fibroblast growth factor receptors leading to the pathogenesis in breast cancer, targeting fibroblast growth factor receptors may provide new opportunities for breast cancer therapeutic strategies.

Heparan sulfate proteoglycans are essential for FGF receptor signaling during Drosophila embryonic development

Development ◽  
1999 ◽  
Vol 126 (17) ◽  
pp. 3715-3723 ◽  
Author(s):  
X. Lin ◽  
E.M. Buff ◽  
N. Perrimon ◽  
A.M. Michelson
Keyword(s):  
Growth Factor ◽  
Heparan Sulfate ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Growth Factor Receptors ◽  
Fibroblast Growth ◽  
Receptor Signaling ◽  
Fibroblast Growth Factor Receptors ◽  
Growth Factor Receptor Signaling

The Drosophila sugarless and sulfateless genes encode enzymes required for the biosynthesis of heparan sulfate glycosaminoglycans. Biochemical studies have shown that heparan sulfate glycosaminoglycans are involved in signaling by fibroblast growth factor receptors, but evidence for such a requirement in an intact organism has not been available. We now demonstrate that sugarless and sulfateless mutant embryos have phenotypes similar to those lacking the functions of two Drosophila fibroblast growth factor receptors, Heartless and Breathless. Moreover, both Heartless- and Breathless-dependent MAPK activation is significantly reduced in embryos which fail to synthesize heparan sulfate glycosaminoglycans. Consistent with an involvement of Sulfateless and Sugarless in fibroblast growth factor receptor signaling, a constitutively activated form of Heartless partially rescues sugarless and sulfateless mutants, and dosage-sensitive interactions occur between heartless and the heparan sulfate glycosaminoglycan biosynthetic enzyme genes. We also find that overexpression of Branchless, the Breathless ligand, can partially overcome the requirement of Sugarless and Sulfateless for Breathless activity. These results provide the first genetic evidence that heparan sulfate glycosaminoglycans are essential for fibroblast growth factor receptor signaling in a well defined developmental context, and support a model in which heparan sulfate glycosaminoglycans facilitate fibroblast growth factor ligand and/or ligand-receptor oligomerization.

scholarly journals Endometrial Cancers Harboring Mutated Fibroblast Growth Factor Receptor 2 Protein Are Successfully Treated With a New Small Tyrosine Kinase Inhibitor in an Orthotopic Mouse Model

2018 ◽  
Vol 28 (1) ◽  
pp. 152-160 ◽  
Author(s):  
Sebastien Taurin ◽  
Chieh-Hsiang Yang ◽  
Maria Reyes ◽  
Sungpil Cho ◽  
Demetrius M. Coombs ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Growth Factor ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Fibroblast Growth Factor ◽  
Kinase Inhibitor ◽  
Growth Factor Receptors ◽  
Fibroblast Growth ◽  
Cancer Model ◽  
Fibroblast Growth Factor Receptors

ObjectivesAL3818 (anlotinib) is a receptor tyrosine kinase inhibitor targeting vascular endothelial growth factor receptors (VEGFR1, VEGFR2/KDR, and VEGFR3), stem cell factor receptor (C-kit), platelet-derived growth factor (PDGFβ), and fibroblast growth factor receptors (FGFR1, FGFR2, and FGFR3). This study evaluates the efficacy of AL3818 studying tumor regression in an orthotopic murine endometrial cancer model.MethodsWe tested the cytotoxicity of AL3818 on a panel of 7 human endometrial cancer cell lines expressing either wild-type or mutant FGFR2 and also assessed the in vivo antitumor efficacy in a murine, orthotopic AN3CA endometrial cancer model. AL3818 was administered daily per os either alone or in combination with carboplatin and paclitaxel, which represent the current standard of adjuvant care for endometrial cancer.ResultsAL3818 significantly reduces AN3CA cell number in vitro, characterized by high expression of a mutated FGFR2 protein. Daily oral administration of AL3818 (5 mg/kg) resulted in a complete response in 55% of animals treated and in a reduced tumor volume, as well as decreased tumor weights of AN3CA tumors by 94% and 96%, respectively, following a 29-day treatment cycle. Whereas carboplatin and paclitaxel failed to alter tumor growth, the combination with AL3818 did not seem to exhibit a superior effect when compared with AL3818 treatment alone.ConclusionsAL3818 shows superior efficacy for the treatment of endometrial cancer irresponsive to conventional carboplatin and paclitaxel combination and warrants further investigation.

scholarly journals Targeting fibroblast growth factor receptors to combat aggressive ependymoma

2021 ◽  
Author(s):  
Daniela Lötsch ◽  
Dominik Kirchhofer ◽  
Bernhard Englinger ◽  
Li Jiang ◽  
Konstantin Okonechnikov ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Molecular Mechanisms ◽  
Radial Glia ◽  
Growth Factor Receptors ◽  
Dominant Negative ◽  
Mrna Levels ◽  
Fibroblast Growth ◽  
Cell Models ◽  
Fibroblast Growth Factor Receptors

AbstractEpendymomas (EPN) are central nervous system tumors comprising both aggressive and more benign molecular subtypes. However, therapy of the high-risk subtypes posterior fossa group A (PF-A) and supratentorial RELA-fusion positive (ST-RELA) is limited to gross total resection and radiotherapy, as effective systemic treatment concepts are still lacking. We have recently described fibroblast growth factor receptors 1 and 3 (FGFR1/FGFR3) as oncogenic drivers of EPN. However, the underlying molecular mechanisms and their potential as therapeutic targets have not yet been investigated in detail. Making use of transcriptomic data across 467 EPN tissues, we found that FGFR1 and FGFR3 were both widely expressed across all molecular groups. FGFR3 mRNA levels were enriched in ST-RELA showing the highest expression among EPN as well as other brain tumors. We further identified high expression levels of fibroblast growth factor 1 and 2 (FGF1, FGF2) across all EPN subtypes while FGF9 was elevated in ST-EPN. Interrogation of our EPN single-cell RNA-sequencing data revealed that FGFR3 was further enriched in cycling and progenitor-like cell populations. Corroboratively, we found FGFR3 to be predominantly expressed in radial glia cells in both mouse embryonal and human brain datasets. Moreover, we detected alternative splicing of the FGFR1/3-IIIc variant, which is known to enhance ligand affinity and FGFR signaling. Dominant-negative interruption of FGFR1/3 activation in PF-A and ST-RELA cell models demonstrated inhibition of key oncogenic pathways leading to reduced cell growth and stem cell characteristics. To explore the feasibility of therapeutically targeting FGFR, we tested a panel of FGFR inhibitors in 12 patient-derived EPN cell models revealing sensitivity in the low-micromolar to nano-molar range. Finally, we gain the first clinical evidence for the activity of the FGFR inhibitor nintedanib in the treatment of a patient with recurrent ST-RELA. Together, these preclinical and clinical data suggest FGFR inhibition as a novel and feasible approach to combat aggressive EPN.

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