Targeted cytotoxic gene delivery to malignant gliomas via the fibroblast growth factor receptor

2000 ◽  
Vol 8 (4) ◽  
pp. 1-8
Author(s):  
Nian-Ling Zhu ◽  
Barbara A. Sosnowski ◽  
Berislav V. Zlokovic ◽  
Michael Ong ◽  
Thomas C. Chen
Keyword(s):  
Gene Therapy ◽  
Endothelial Cells ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Marker Gene ◽  
Malignant Gliomas ◽  
Glioma Cells ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Fibroblast Growth ◽  
Fibroblast Growth Factor Receptors

Object The use of gene therapy for the treatment of malignant gliomas has been disappointing. In an effort to increase the viral transduction efficiency in delivering cytotoxic genes to malignant gliomas, the authors have used a novel retargeting schema that redirects the adenovirus to fibroblast growth factor receptors present on the cell surface of both proliferating glioma cells and glioma endothelial cells. Methods Using this targeted adenovirus, the authors demonstrated an increase in expression of the luciferase marker gene in human glioma cells and glioma endothelial cells. Transduction with the herpes simplex thymidine kinase gene resulted in greater cytotoxicity when treated with ganciclovir for both cell types. This increased cytotoxity was sustained for up to 6 days after administration of ganciclovir. Conclusions The mechanism of cytotoxicity was determined to be apoptosis by using the terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick-end labeling assay. Increasing the specificity of adenovirus targeting may be crucial to decrease the number of adenoviral vectors necessary to create adequate levels of gene transfer in malignant gliomas, thus reducing the risk of vector-related immunogenicity and toxicity, as well as increasing the overall effectiveness of cytotoxic gene therapy.

Retargeting of adenoviral vector using basic fibroblast growth factor ligand for malignant glioma gene therapy

2005 ◽  
Vol 103 (6) ◽  
pp. 1058-1066 ◽  
Author(s):  
Weijun Wang ◽  
Nian-Ling Zhu ◽  
Jason Chua ◽  
Steve Swenson ◽  
Fritz K. Costa ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Cell Lines ◽  
Malignant Gliomas ◽  
Glioma Cells ◽  
Transduction Efficiency ◽  
Fibroblast Growth ◽  
Content Type ◽  
Fine Print

Object. Adenovirus vector (AdV)—mediated gene delivery has been recently demonstrated in clinical trials as a novel potential treatment for malignant gliomas. Combined coxsackievirus B and adenovirus receptor (CAR) has been shown to function as an attachment receptor for multiple adenovirus serotypes, whereas the vitronectin integrins (αvβ3 and αvβ5) are involved in AdV internalization. In resected glioma specimens, the authors demonstrated that malignant gliomas have varying levels of CAR, αvβ3, and αvβ5 expression. Methods. A correlation between CAR expression and the transduction efficiency of AdV carrying the green fluorescent protein in various human glioblastoma multiforme (GBM) cell lines and GBM primary cell lines was observed. To increase transgene activity in in vitro glioma cells with low or deficient levels of CAR, the authors used basic fibroblast growth factor (FGF2) as a targeting ligand to redirect adenoviral infection through its cognate receptor, FGF receptor 1 (FGFR1), which was expressed at high levels by all glioma cells. These findings were confirmed by in vivo study data demonstrating enhanced transduction efficiency of FGF2-retargeted AdV in CAR-negative intracranial gliomas compared with AdV alone, without evidence of increased angiogenesis. Conclusions. Altogether, the results demonstrated that AdV-mediated gene transfer using the FGF2/FGFR system is effective in gliomas with low or deficient levels of CAR and suggested that FGF2-retargeting of AdV may be a promising approach in glioma gene therapy.

Delivery of Human Fibroblast Growth Factor-1 Gene to Brain by Modified Rat Brain Endothelial Cells

2002 ◽  
Vol 67 (4) ◽  
pp. 1643-1652 ◽  
Author(s):  
P. Johnston ◽  
M. Nam ◽  
M. A. Hossain ◽  
R. R. Indurti ◽  
J. L. Mankowski ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Rat Brain ◽  
Fibroblast Growth Factor ◽  
Human Fibroblast ◽  
Fibroblast Growth ◽  
Brain Endothelial Cells ◽  
Rat Brain Endothelial Cells

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.

scholarly journals Current Status of Fibroblast Growth Factor Receptor-Targeted Therapies in Breast Cancer

Cells ◽  
2018 ◽  
Vol 7 (7) ◽  
pp. 76 ◽  
Author(s):  
Navid Sobhani ◽  
Anna Ianza ◽  
Alberto D’Angelo ◽  
Giandomenico Roviello ◽  
Fabiola Giudici ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Metastatic Breast ◽  
Tumor Formation ◽  
Current Status ◽  
Fibroblast Growth ◽  
Fibroblast Growth Factor Receptors

Breast cancer (BC) is the most common malignancy and second only to lung cancer in terms of mortality in women. Despite the incredible progress made in this field, metastatic breast cancer has a poor prognosis. In an era of personalized medicine, there is an urgent need for better knowledge of the biology leading to the disease, which can lead to the design of increasingly accurate drugs against patients’ specific molecular aberrations. Among one of the actionable targets is the fibroblast growth factor receptor (FGFR) pathway, triggered by specific ligands. The Fibroblast Growth Factor Receptors/Fibroblast Growth Factors (FGFRs/FGFs) axis offers interesting molecular targets to be pursued in clinical development. This mini-review will focus on the current knowledge of FGFR mutations, which lead to tumor formation and summarizes the state-of-the-art therapeutic strategies for targeted treatments against the FGFRs/FGFs axis in the context of BC.

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