Academic Journal
Pharmacologic reprogramming of virus-tumor crosstalk enhances measles virus antitumor activity in BRAF mutant colorectal cancer models.
| Τίτλος: | Pharmacologic reprogramming of virus-tumor crosstalk enhances measles virus antitumor activity in BRAF mutant colorectal cancer models. |
|---|---|
| Συγγραφείς: | Chavez V; Department of Medicine, Division of Medical Oncology, University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center, Miami, FL, USA., Montero M; Department of Medicine, Division of Medical Oncology, University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center, Miami, FL, USA., Tran NHG; Department of Medicine, Division of Medical Oncology, University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center, Miami, FL, USA., Mendes CM; University of Miami College of Arts and Sciences, Miami, FL, USA., Ban Y; Department of Public Health Sciences, Division of Biostatistics, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA., Khurana R; Department of Public Health Sciences, Division of Biostatistics, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA., Ceccarelli M; Department of Public Health Sciences, Division of Biostatistics, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA., Merchan JR; Department of Medicine, Division of Medical Oncology, University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center, Miami, FL, USA. Jmerchan2@med.miami.edu. |
| Πηγή: | Journal of experimental & clinical cancer research : CR [J Exp Clin Cancer Res] 2026 Jun 06; Vol. 45 (1). Date of Electronic Publication: 2026 Jun 06. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: BioMed Central Country of Publication: England NLM ID: 8308647 Publication Model: Electronic Cited Medium: Internet ISSN: 1756-9966 (Electronic) Linking ISSN: 03929078 NLM ISO Abbreviation: J Exp Clin Cancer Res Subsets: MEDLINE |
| Imprint Name(s): | Publication: 2009- : London : BioMed Central Original Publication: [Roma] : APSIT |
| Ιατρικοί όροι (MeSH): | Measles virus*/physiology , Colorectal Neoplasms*/genetics , Colorectal Neoplasms*/therapy , Colorectal Neoplasms*/pathology , Colorectal Neoplasms*/drug therapy , Colorectal Neoplasms*/virology , Oncolytic Virotherapy*/methods , Proto-Oncogene Proteins B-raf*/genetics , Diterpenes*/pharmacology , Diterpenes*/therapeutic use , Phenanthrenes*/pharmacology , Phenanthrenes*/therapeutic use, Epoxy Compounds/pharmacology ; Epoxy Compounds/therapeutic use ; Humans ; Animals ; Mice ; Xenograft Model Antitumor Assays ; Mutation ; Cell Line, Tumor ; Oncolytic Viruses |
| Περίληψη: | Background: Oncolytic viruses are promising cancer biotherapies but often show limited durability as single agents due to tumor-intrinsic resistance mechanisms. Because therapeutic efficacy is shaped by dynamic virus-tumor-stromal interactions, pharmacologic strategies that reprogram this interface may enhance virotherapy responses. Here, we investigate whether targeting tumor stress and survival pathways with triptolide and its prodrug Minnelide can enhance the oncolytic efficacy of measles virus in colorectal cancer. 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 HT29 and HCT116 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 V600E mutant CRC cell lines, and modulated key cancer pathways including AKT, 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 significantly enhance the oncolytic efficacy of measles virus in colorectal cancer, particularly in BRAF-mutant tumors in vivo, through reprogramming of virus-tumor-stromal interactions. This reprogramming arises from coordinated modulation of survival, metabolic, and stromal signaling pathways and is accompanied by improved intratumoral viral distribution. These findings position virus-tumor-stromal crosstalk as a central mechanistic axis of virotherapy response and provide a strong rationale for the translational and clinical development of rational virus-drug combination strategies in colorectal cancer and other malignancies. (© 2026. The Author(s).) |
| Competing Interests: | Declarations. Ethics approval and consent to participate: This study was conducted in accordance with institutional guidelines for animal care and use. All animal experiments were approved by the Institutional Animal Care and Use Committee (IACUC) of University of Miami, under protocol number 20–130 LF. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests. |
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| Grant Information: | P30 CA240139 United States CA NCI NIH HHS; 20B13/AWD-006055 Bankhead-Coley Foundation |
| Contributed Indexing: | Keywords: BRAF mutation; Colorectal cancer; Measles virus; Minnelide; Molecular mechanisms; Oncolytic virotherapy; Tumor stroma |
| Substance Nomenclature: | EC 2.7.11.1 (Proto-Oncogene Proteins B-raf) EC 2.7.11.1 (BRAF protein, human) 19ALD1S53J (triptolide) 0 (Epoxy Compounds) 0 (Diterpenes) 0 (Phenanthrenes) |
| Entry Date(s): | Date Created: 20260606 Date Completed: 20260902 Latest Revision: 20260904 |
| Update Code: | 20260904 |
| PubMed Central ID: | PMC13536603 |
| DOI: | 10.1186/s13046-026-03749-9 |
| PMID: | 42251341 |
| Βάση Δεδομένων: | MEDLINE |
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