Novel Fusion Protein Based on DR5-Specific TRAIL Variant with Enhanced Antitumor Properties

Area of Science:

• Oncology
• Molecular Biology
• Biotechnology

Background:

• Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis in cancer cells.
• First-generation TRAIL agonists demonstrated limited clinical antitumor activity.
• Targeting both tumor cells and the tumor microenvironment is crucial for enhanced efficacy.

Purpose of the Study:

• To develop a multitarget recombinant fusion protein, SRH-DR5-B-p48, for enhanced cancer therapy.
• To simultaneously induce apoptosis via DR5 and suppress angiogenesis by targeting VEGFR2 and FGFR1.
• To evaluate the efficacy of SRH-DR5-B-p48 in preclinical cancer models.

Main Methods:

• Designed and produced the SRH-DR5-B-p48 fusion protein.
• Utilized molecular dynamics to analyze peptide-receptor interactions.
• Employed enzyme-linked immunosorbent assay (ELISA) to assess binding affinities.
• Evaluated cytotoxicity and anti-angiogenic effects in 3D cell models.

Main Results:

• SRH-DR5-B-p48 exhibited high affinity for DR5, VEGFR2, and FGFR1.
• The fusion protein demonstrated enhanced tumor cell killing compared to DR5-B.
• SRH-DR5-B-p48 effectively disrupted tumor-like structures and inhibited fibroblast proliferation.
• Molecular dynamics suggested non-specific interactions between peptides and the DR5-B domain.

Conclusions:

• SRH-DR5-B-p48 is a potent multitarget agent for cancer therapy.
• The fusion protein effectively targets tumor cells and inhibits angiogenesis.
• SRH-DR5-B-p48 shows significant potential for treating solid tumors.