Intravesical instillation-based mTOR-STAT3 dual targeting for bladder cancer treatment

Area of Science:

• Oncolytic virotherapy
• Gene therapy
• Bladder cancer research

Background:

• Adenoviral vectors show promise for non-muscle invasive bladder cancer (NMIBC).
• Current treatments struggle with intracellular cancer cell survival signaling.
• Immune checkpoint inhibitors are used alongside adenoviral vectors.

Purpose of the Study:

• To address intracellular survival signaling in bladder cancer.
• To develop a dual siRNA system targeting mTOR and STAT3.
• To enhance in vivo delivery of siRNA using adenovirus 5/3 (Ad 5/3).

Main Methods:

• Designed a dual siRNA system targeting mTOR and STAT3 mRNAs.
• Encoded the dual siRNA system into Ad 5/3 for improved delivery.
• Assessed gene-targeting efficacy using single-cell analysis in vitro and in vivo.

Main Results:

• Achieved balanced downregulation of mTOR and STAT3 at the single-cell level.
• Reduced tumor growth in bladder cancer xenograft and orthotopic models.
• Observed increased CD8+ T cell infiltration in a humanized mouse model.
• Provided safe tissue distribution data for intravesical siRNA-adenovirus therapy.

Conclusions:

• Bi-specific siRNA encapsulated in adenovirus is a promising strategy for cancer treatment.
• This approach can overcome limitations of conventional therapies, including "undruggability".
• Dual targeting of mTOR and STAT3 via adenovirus-mediated intravesical therapy is advantageous.