Suppression of tumor growth and metastasis by a VEGFR-1 antagonizing peptide identified from a phage display library

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Vascular Endothelial Growth Factor (VEGF) and its receptor pathway (VEGF-Flk-1) are key drivers of angiogenesis.
• Emerging evidence highlights the critical role of VEGFR-1/Flt-1 in pathological neovascularization, including in tumors, atherosclerosis, and arthritis.

Purpose of the Study:

• To identify peptides that antagonize the Flt-1 receptor.
• To evaluate the antiangiogenic and antimetastatic potential of identified peptides, particularly F56.

Main Methods:

• Screening of a phage display 12-mer-peptide library using recombinant Flt-1 protein.
• In vitro assessment of peptide binding to Flt-1 and inhibition of VEGF binding.
• In vivo evaluation of peptide efficacy using chick chorioallantoic membrane (CAM) assay, gastric cancer xenograft models, and breast cancer metastasis models in mice.

Main Results:

• Seven peptides specifically binding to Flt-1 were identified; peptide F56 demonstrated potent inhibition of VEGF binding to Flt-1 in vitro.
• DHFR-F56 fusion protein inhibited angiogenesis in the CAM assay and significantly suppressed gastric tumor growth and enhanced necrosis in mice.
• Synthetic F56 significantly inhibited tumor growth and lung metastasis in a human breast cancer cell line xenograft model.

Conclusions:

• Peptide F56 acts as a Flt-1 receptor antagonist, exhibiting antiangiogenic and antimetastatic effects by disrupting VEGF-Flt-1 interaction.
• Peptide F56 demonstrates significant therapeutic potential for cancer treatment, warranting further clinical investigation.