Innovative dual system approach for selective eradication of cancer cells using viral-based delivery of natural...

Area of Science:

• Molecular Biology
• Cancer Genetics
• Bacterial Toxin-Antitoxin Systems

Background:

• Frequent genetic alterations in cancer include p53 inactivation and RAS oncogene activation.
• Targeting these specific mutations is crucial for effective cancer therapy.
• Bacterial toxin-antitoxin (TA) systems offer potential for targeted cell killing.

Purpose of the Study:

• To develop and validate a novel platform for selective cancer cell eradication using a bacterial MazF-MazE TA system.
• To engineer adenoviral vectors for delivering the MazF toxin and MazE antitoxin regulated by RAS and p53 pathways.
• To assess the efficacy of this system in vitro and in vivo for RAS-mutated cancers.

Main Methods:

• Construction of adenoviral vectors carrying the MazF toxin and MazE antitoxin under RAS and p53-responsive elements.
• Co-infection of HCT116 cancer cell lines (KRAS/p53 mutated) with engineered adenoviral vectors.
• In vivo studies involving tumor implantation and treatment with the MazF-MazE system and control vectors.

Main Results:

• The MazF-MazE TA system induced significant, dose-dependent cell death in vitro (69% vs. 19% in control).
• In vivo, the system achieved substantial tumor growth inhibition in HCT116 (KRASmut/p53mut) tumors (73% vs. PBS).
• Demonstrated 65% tumor growth inhibition in HCT116 (KRASmut/p53wt) cells, highlighting the antitoxin's role in protecting normal cells.

Conclusions:

• The study provides proof of concept for a novel platform to selectively eradicate cancer cells based on p53 and RAS mutations.
• The MazF-MazE TA system, delivered via adenoviral vectors, is effective in inhibiting tumor growth both in vitro and in vivo.
• The antitoxin component (MazE) is crucial for protecting normal cells from potential toxin leakage and enhancing system specificity.