Non-transmissible Sendai virus vector encoding c-myc suppressor FBP-interacting repressor for cancer therapy

Area of Science:

• Oncology
• Molecular Biology
• Gene Therapy

Background:

• The c-myc oncogene is frequently overexpressed in human cancers, driving tumor growth and progression.
• Targeting c-myc is a critical therapeutic goal, but effective strategies remain limited.
• Far upstream element (FUSE)-binding protein-interacting repressor (FIR) has been identified as a potential regulator of c-myc transcription.

Purpose of the Study:

• To investigate the therapeutic potential of FIR as a novel strategy to suppress c-myc in human cancers.
• To evaluate the efficacy of FIR-expressing viral vectors in inducing apoptosis and inhibiting tumor growth in preclinical models.

Main Methods:

• Development and characterization of a Sendai virus (SeV) vector (SeV/dF/FIR) encoding FIR cDNA.
• Assessment of gene transduction efficiency, dose-dependent antitumor effects, and apoptosis induction in cervical (HeLa) and colon (SW480) cancer cell lines.
• Evaluation of antitumor efficacy in a mouse xenograft model.
• Investigation of the molecular mechanisms underlying c-myc suppression and antitumor effects, including the role of SAP155 and FIR splicing variants.

Main Results:

• FIR was confirmed to repress c-myc transcription, and its overexpression induced apoptosis via c-myc suppression.
• The SeV/dF/FIR vector demonstrated high gene transduction efficiency and potent antitumor effects in vitro and in vivo.
• SeV/dF/FIR suppressed elevated c-myc levels and induced significant apoptosis in cancer cells, with no observed major side effects in a mouse xenograft model.
• Alternative splicing of FIR (FIR∆exon2) by SAP155 was identified as a mechanism that can counteract FIR's tumor-suppressive function.

Conclusions:

• The FIR-expressing SeV/dF/FIR vector represents a promising gene therapy approach for cancer treatment.
• FIR effectively suppresses tumor growth by targeting c-myc and inducing apoptosis.
• Further investigation into the modulation of FIR splicing by SAP155 is warranted for optimizing therapeutic strategies.