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

ABSTRACT: Background. Oncolytic viruses represent promising cancer biotherapies due to their ability to selectively lyse tumor cells and stimulate anti-tumor immune responses. However, their long-term efficacy as single agents is inconsistent, underscoring the need for virus-drug combinations to improve outcomes. This study evaluates the effects and mechanisms of triptolide and minnelide in enhancing measles virus oncolysis in human colorectal cancer (CRC) models. Methods. The in vitro effects of CD46 targeted (MV-GFP) and dual targeted (MV-CD46-muPA) oncolytic MV, alone and with triptolide were assessed in human CRC cell lines. 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE312474 | GEO | 2026/07/31

REPOSITORIES: GEO

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Project description:Previously we reported that a recombinant vaccinia virus (VACV) carrying a light-emitting fusion gene enters, replicates in, and reveals the locations of tumors in mice. A new recombinant VACV, GLV-1h68, as a simultaneous diagnostic and therapeutic agent, was constructed by inserting three expression cassettes (encoding Renilla luciferase-green fluorescent protein (RUC-GFP) fusion, b-galactosidase, and b-glucuronidase) into the F14.5L, J2R (encoding thymidine kinase, TK), and A56R (encoding hemagglutinin, HA) loci of the viral genome, respectively. Intravenous (i.v.) injections of GLV-1h68 (1 Ã 107 pfu/mouse) into nude mice with established (500 mm3) subcutaneous (s.c.) GI-101A human breast tumors were used to evaluate its toxicity, tumor targeting specificity and oncolytic efficacy. GLV-1h68 demonstrated an enhanced tumor targeting specificity and much reduced toxicity compared to its parental LIVP strains. The tumors colonized by GLV-1h68 exhibited growth, inhibition, and regression phases followed by tumor eradication within 130 days in 95% of the mice tested. Tumor regression in live animals was monitored in real time based on decreasing light emission, hence demonstrating the concept of a combined oncolytic virus-mediated tumor diagnosis and therapy system. Transcriptional profiling of regressing tumors based on a mouse-specific platform revealed gene expression signatures consistent with immune defense activation, inclusive of interferon stimulated genes (STAT-1 and IRF-7), cytokines, chemokines and innate immune effector function. These findings suggest that immune activation may combine with viral oncolysis to induce tumor eradication in this model, providing a novel perspective for the design of oncolytic viral therapies for human cancers. Objective: To determine the gene expression changes induced by GLV-1h68 vaccinia virus injection in mouse carrying human breast cancer implant and leading to tumor eradication. Methods: Gene expression was analyzed using oligonucleotide microarrays. Responsiveness to vaccina virus injection was assessed by toxicity and survival study, gene expression anaysis and tumor volume change. Result: The tumors colonized by GLV-1h68 exhibited growth, inhibition, and regression phases followed by tumor eradication within 130 days in 95% of the mice tested. Tumor regression in live animals was monitored in real time based on decreasing light emission, hence demonstrating the concept of a combined oncolytic virus-mediated tumor diagnosis and therapy system. Transcriptional profiling of regressing tumors based on a mouse-specific platform revealed gene expression signatures consistent with immune defense activation, inclusive of interferon stimulated genes (STAT-1 and IRF-7), cytokines, chemokines and innate immune effector function. Conclusion: Our findings suggest that immune activation may combine with viral oncolysis to induce tumor eradication in this model, providing a novel perspective for the design of oncolytic viral therapies for human cancers. Experiment Overall Design: tumor tissues 3 and 6 weeks post virus injection

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

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