Abstract P238: Derazantinib, an inhibitor of fibroblast growth factor receptors 1-3, synergises with paclitaxel in pre-clinical gastric tumor models

2021 ◽  
Author(s):  
Paul M. McSheehy ◽  
Mahmoud El Shemerly ◽  
Felix Bachmann ◽  
Laurenz Kellenberger ◽  
Heidi Lane
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Growth Factor Receptors ◽  
Gastric Tumor ◽  
Fibroblast Growth ◽  
Fibroblast Growth Factor Receptors ◽  
Tumor Models

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.

Semirational design of a potent, artificial agonist of fibroblast growth factor receptors

10.1038/70746 ◽  
1999 ◽  
Vol 17 (12) ◽  
pp. 1199-1204 ◽  
Author(s):  
Marcus D. Ballinger ◽  
Venkatakrishna Shyamala ◽  
Louise D. Forrest ◽  
Maja Deuter-Reinhard ◽  
Laura V. Doyle ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Growth Factor Receptors ◽  
Fibroblast Growth ◽  
Fibroblast Growth Factor Receptors

scholarly journals Role of Klotho in Hyperglycemia: Its Levels and Effects on Fibroblast Growth Factor Receptors, Glycolysis, and Glomerular Filtration

2021 ◽  
Vol 22 (15) ◽  
pp. 7867
Author(s):  
Marlena Typiak ◽  
Tomasz Kulesza ◽  
Patrycja Rachubik ◽  
Dorota Rogacka ◽  
Irena Audzeyenka ◽  
...  
Keyword(s):  
Growth Factor ◽  
Urinary Excretion ◽  
Glomerular Filtration ◽  
Fibroblast Growth Factor ◽  
Growth Factor Receptors ◽  
Renal Tissue ◽  
Proper Function ◽  
Fibroblast Growth ◽  
Fibroblast Growth Factor Receptors ◽  
Plasma Filtration

Hyperglycemic conditions (HG), at early stages of diabetic nephropathy (DN), cause a decrease in podocyte numbers and an aberration of their function as key cells for glomerular plasma filtration. Klotho protein was shown to overcome some negative effects of hyperglycemia. Klotho is also a coreceptor for fibroblast growth factor receptors (FGFRs), the signaling of which, together with a proper rate of glycolysis in podocytes, is needed for a proper function of the glomerular filtration barrier. Therefore, we measured levels of Klotho in renal tissue, serum, and urine shortly after DN induction. We investigated whether it influences levels of FGFRs, rates of glycolysis in podocytes, and albumin permeability. During hyperglycemia, the level of membrane-bound Klotho in renal tissue decreased, with an increase in the shedding of soluble Klotho, its higher presence in serum, and lower urinary excretion. The addition of Klotho increased FGFR levels, especially FGFR1/FGFR2, after their HG-induced decrease. Klotho also increased levels of glycolytic parameters of podocytes, and decreased podocytic and glomerular albumin permeability in HG. Thus, we found that the decrease in the urinary excretion of Klotho might be an early biomarker of DN and that Klotho administration may have several beneficial effects on renal function in DN.

Mapping of Murine Fibroblast Growth Factor Receptors Refines Regions of Homology between Mouse and Human Chromosomes

Genomics ◽  
1994 ◽  
Vol 21 (3) ◽  
pp. 656-658 ◽  
Author(s):  
Karen B. Avraham ◽  
David Givol ◽  
Aaron Avivi ◽  
Avner Yayon ◽  
Neal G. Copeland ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Growth Factor Receptors ◽  
Fibroblast Growth ◽  
Human Chromosomes ◽  
Fibroblast Growth Factor Receptors ◽  
Murine Fibroblast
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