MODULATION OF VIRUS–TUMOR-STROMAL INTERACTIONS BY MINNELIDE ENHANCES SYSTEMIC DUAL TARGETED MEASLES VIROTHERAPY IN BRAF-MUTANT COLORECTAL CANCER

Mechanistic studies included gene expression analysis, functional proteomics, and western blotting. In vivo efficacy of MV-CD46-muPA combined with minnelide was evaluated in HT-29 and HCT-116 xenografts. Biological effects were further characterized using transcriptomic profiling (RNA-seq), targeted gene expression (NanoString), and histological analysis .

Results. Triptolide enhanced MV mediated oncolysis in vitro, particularly in BRAF mutant CRC cell lines, and modulated cancer pathways including AKT, autophagy, apoptosis and metabolism. In vivo, minnelide significantly improved the efficacy of systemically administered MV-CD46-muPA in human CRC xenografts, with greater effects in BRAF mutant (HT29) models.

The combination modulated cell cycle, metabolism, and survival associated genes, promoted apoptosis, and improved intratumoral viral distribution. These molecular effects resulted in reduced tumor cell proliferation (Ki67), decreased angiogenesis (CD31) and increased apoptosis (TUNEL) relative to single agents. Conclusion.

Triptolide and minnelide synergistically enhance the antitumor efficacy of oncolytic measles virus in colorectal cancer, particularly in BRAF mutant tumors through modulation of survival, metabolism and stromal pathways, together with improved viral distribution. These findings underscore the innovative potential of this virus-drug combination and support further translational development for CRC and other malignancies.