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Screening and Identification of Small Peptides Targeting Fibroblast Growth Factor Receptor2 using a Phage Display Peptide Library
Published on: September 30, 2019
Evaluation of the fibroblast growth factor system as a potential target for therapy in human prostate cancer
B Gowardhan1, D A Douglas, M E Mathers
1Urology Research Group, Northern Institute for Cancer Research, University of Newcastle, Newcastle upon Tyne, NE2 4HH, UK.
Abstract:
Overexpression of fibroblast growth factors (FGFs) has been implicated in prostate carcinogenesis. FGFs function via their high-affinity interactions with receptor tyrosine kinases, FGFR1-4. Expression of FGFR1 and FGFR2 in prostate cancer (CaP) was not found to be associated with clinical parameters. In this report, we further investigated for abnormal FGFR expression in prostate cancer and explore their significance as a potential target for therapy. The expression levels of FGFR3 and FGFR4 in CaP were examined and corroborated to clinical parameters. FGFR3 immunoreactivity in benign prostatic hyperplasia (BPH) and CaP (n=26 and 57, respectively) had similar intensity and pattern. Overall, FGFR4 expression was significantly upregulated in CaP when compared to BPH. A significant positive correlation between FGFR4 expression and Gleason score was noted: Gleason score 7-10 tumours compared to BPH (P<0.0001, Fisher's exact test), Gleason score 4-6 tumours compared to BPH (P<0.0004), and Gleason 7-10 compared to Gleason 4-6 tumours (P<0.005). FGFR4 overexpression was associated with an unfavourable outcome with decreased disease-specific survival (P<0.04, log rank test). FGF-induced signalling is targeted using soluble FGF receptor (sFGFR), potent inhibitor of FGFR function. We have previously shown that sFGFR expression via a replication-deficient adenoviral vector (AdlllcRl) suppresses in vitro FGF-induced signalling and function in human CaP DU145 cells. We tested the significance of inhibiting FGF function along with conventional therapeutic modalities in CaP, and confirmed synergistic effects on in vitro cell growth (proliferation and colony formation) by combining sFGFR expression and treatment with either Paclitaxel (Taxol) or gamma-irradiation. In summary, our data support the model of FGF system as valid target for therapy in CaP.
Insights
Fibroblast growth factor receptor 4 (FGFR4) is overexpressed in prostate cancer (CaP) and linked to poor outcomes. Inhibiting FGF signaling with soluble FGFR (sFGFR) synergizes with chemotherapy, offering a potential CaP therapeutic strategy.
Area of Science:
- Molecular Oncology
- Prostate Cancer Research
- Receptor Tyrosine Kinase Signaling
Background:
- Fibroblast growth factors (FGFs) and their receptors (FGFRs) are implicated in prostate cancer (CaP) development.
- While FGFR1 and FGFR2 expression lacks clinical correlation, the roles of FGFR3 and FGFR4 in CaP require further investigation.
- Targeting FGF signaling pathways presents a potential therapeutic avenue for CaP.
Purpose of the Study:
- To investigate the expression levels of FGFR3 and FGFR4 in prostate cancer (CaP) and their correlation with clinical parameters.
- To evaluate the therapeutic potential of inhibiting FGF signaling, specifically using soluble FGFR (sFGFR), in combination with conventional treatments.
- To assess the significance of FGFR4 as a potential therapeutic target in CaP.
Main Methods:
- Immunohistochemical analysis of FGFR3 and FGFR4 expression in benign prostatic hyperplasia (BPH) and CaP tissues (n=26 BPH, n=57 CaP).
- Correlation analysis between FGFR4 expression, Gleason score, and disease-specific survival.
- In vitro studies using adenoviral vector-mediated sFGFR expression in human CaP DU145 cells, combined with Paclitaxel or gamma-irradiation.
Main Results:
- FGFR3 expression showed similar patterns in BPH and CaP.
- FGFR4 expression was significantly upregulated in CaP compared to BPH.
- FGFR4 overexpression positively correlated with higher Gleason scores and was associated with decreased disease-specific survival.
- Combined sFGFR expression with Paclitaxel or gamma-irradiation demonstrated synergistic effects on CaP cell growth inhibition (proliferation and colony formation).
Conclusions:
- FGFR4 is significantly overexpressed in prostate cancer and serves as a prognostic marker for unfavorable outcomes.
- Inhibition of FGF signaling via sFGFR shows synergistic effects when combined with conventional therapies like Paclitaxel and gamma-irradiation.
- The FGF signaling system represents a promising therapeutic target for prostate cancer treatment.
