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Targeted Inhibition of Colorectal Carcinoma Using a Designed CEA-Binding Protein to Deliver p53 Protein and TCF/LEF
Wen Wang1, Xuan Sun1, Geng Wu1
1State Key Laboratory of Microbial Metabolism, School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China.
Abstract:
Colorectal carcinoma (CRC) is characterized by mutations in p53 and the Wnt signaling pathway, and immunotherapy has shown limited efficacy in microsatellite-stable CRC. Here, CEABP1, a binding protein for the CRC biomarker carcinoembryonic antigen (CEA), was designed de novo through the AI-based computational generation methods RFDiffusion/ProteinMPNN and stringent in silico selection, for targeted delivery of purified p53 protein and transcription factor T-cell factor (TCF)/lymphoid enhancer-binding factor (LEF) transcription factor decoy (TFD) DNA into CRC cells. The cell-penetrating peptide (CPP) p28 was employed to deliver the p28-p53-CEABP1 protein, which significantly enhanced p53's inhibition of CRC cell proliferation and xenograft tumor growth. Codelivery of the p14ARF protein together with p53 prolonged the effective antitumor duration of p53. In addition, the DNA binding domain of Max was fused with CPP and CEABP1 to deliver TCF/LEF TFD DNA, comprising concatenated consensus binding motifs for TCF/LEF and Max, into CRC cells to inhibit Wnt target gene transcription, leading to marked suppression of CRC cell proliferation and xenograft tumor growth. These findings paved the way for the development of precision anticancer therapeutics using designed binding proteins of tumor biomarkers for targeted delivery of tumor suppressor proteins and TFD DNA.
Insights
AI-designed binding proteins target colorectal cancer (CRC) by delivering tumor suppressors like p53 and Wnt pathway inhibitors. This approach shows promise for precision therapeutics in microsatellite-stable CRC.
Area of Science:
- Oncology
- Biotechnology
- Protein Engineering
Background:
- Colorectal carcinoma (CRC) often involves p53 mutations and Wnt pathway activation.
- Immunotherapy efficacy is limited in microsatellite-stable CRC.
- Targeted delivery of therapeutic agents is crucial for CRC treatment.
Purpose of the Study:
- To design novel binding proteins for targeted delivery of therapeutic payloads into CRC cells.
- To evaluate the efficacy of AI-designed proteins for delivering p53 and Wnt pathway inhibitors.
- To develop precision anticancer therapeutics for CRC.
Main Methods:
- AI-based de novo protein design (RFDiffusion/ProteinMPNN) and in silico selection.
- Engineering CEABP1 as a binding protein for carcinoembryonic antigen (CEA).
- Utilizing cell-penetrating peptide (CPP) p28 for protein delivery and fusion proteins for DNA delivery.
Main Results:
- p28-p53-CEABP1 protein delivery significantly inhibited CRC cell proliferation and xenograft tumor growth.
- Co-delivery of p14ARF with p53 extended the antitumor effect.
- Delivered TCF/LEF transcription factor decoy (TFD) DNA suppressed Wnt target gene transcription and CRC growth.
Conclusions:
- AI-designed binding proteins enable targeted delivery of tumor suppressor proteins and transcription factor decoys.
- This strategy offers a novel approach for precision anticancer therapeutics in CRC.
- The developed platform holds potential for treating microsatellite-stable CRC.
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