In vivo self-assembled siRNAs targeting VEGFR2 and mTOR for renal cell carcinoma treatment

Area of Science:

• Oncology
• Molecular Biology
• Biotechnology

Background:

• Renal cell carcinoma (RCC) presents significant challenges due to its aggressive behavior, including metastasis and resistance to treatments.
• Current combination therapies for advanced RCC, such as sunitinib and everolimus, demonstrate efficacy but are associated with severe adverse effects.

Purpose of the Study:

• To develop and evaluate a novel multi-targeted therapy for clear cell renal cell carcinoma (ccRCC).
• To engineer a liver-based bioreactor system for in vivo production and delivery of self-assembled siRNAs (IVSA-siRNAs).
• To assess the therapeutic efficacy and toxicity of IVSA-siRNAs targeting VEGFR2 and mTOR in preclinical ccRCC models.

Main Methods:

• Establishment of advanced ccRCC models using orthotopic tumor transplantation and post-surgical recurrence models via radical nephrectomy in mice.
• Engineering a genetic circuit to reprogram the host liver into a bioreactor for IVSA-siRNA production and delivery.
• Co-targeting of VEGFR2 and mTOR pathways using IVSA-siRNAs and comparison with sunitinib/everolimus combination therapy.

Main Results:

• The IVSA-siRNA system effectively silenced VEGFR2 and mTOR expression in established ccRCC models.
• Therapeutic effects were observed in both advanced and post-nephrectomy recurrent ccRCC models.
• IVSA-siRNA treatment demonstrated significant therapeutic benefits without inducing discernible toxicity, unlike conventional combination therapy.

Conclusions:

• The engineered IVSA-siRNA system offers a promising, non-toxic therapeutic strategy for advanced and recurrent renal cell carcinoma.
• Reprogramming the liver as a bioreactor for targeted siRNA delivery represents a novel approach for cancer therapy.
• This innovative approach warrants further investigation for clinical translation in treating ccRCC.