Intra-cavity stem cell therapy inhibits tumor progression in a novel murine model of medulloblastoma surgical resection.

Academic Article

Abstract

  • BACKGROUND: Cytotoxic neural stem cells (NSCs) have emerged as a promising treatment for Medulloblastoma (MB), the most common malignant primary pediatric brain tumor. The lack of accurate pre-clinical models incorporating surgical resection and tumor recurrence limits advancement in post-surgical MB treatments. Using cell lines from two of the 5 distinct MB molecular sub-groups, in this study, we developed an image-guided mouse model of MB surgical resection and investigate intra-cavity NSC therapy for post-operative MB. METHODS: Using D283 and Daoy human MB cells engineered to express multi-modality optical reporters, we created the first image-guided resection model of orthotopic MB. Brain-derived NSCs and novel induced NSCs (iNSCs) generated from pediatric skin were engineered to express the pro-drug/enzyme therapy thymidine kinase/ganciclovir, seeded into the post-operative cavity, and used to investigate intra-cavity therapy for post-surgical MB. RESULTS: We found that surgery reduced MB volumes by 92%, and the rate of post-operative MB regrowth increased 3-fold compared to pre-resection growth. Real-time imaging showed NSCs rapidly homed to MB, migrating 1.6-fold faster and 2-fold farther in the presence of tumors, and co-localized with MB present in the contra-lateral hemisphere. Seeding of cytotoxic NSCs into the post-operative surgical cavity decreased MB volumes 15-fold and extended median survival 133%. As an initial step towards novel autologous therapy in human MB patients, we found skin-derived iNSCs homed to MB cells, while intra-cavity iNSC therapy suppressed post-surgical tumor growth and prolonged survival of MB-bearing mice by 123%. CONCLUSIONS: We report a novel image-guided model of MB resection/recurrence and provide new evidence of cytotoxic NSCs/iNSCs delivered into the surgical cavity effectively target residual MB foci.
  • Authors

    Published In

  • PLoS ONE  Journal
  • Keywords

  • Animals, Brain, Brain Neoplasms, Cell Differentiation, Cell Movement, Cell- and Tissue-Based Therapy, Disease Models, Animal, Enzyme Therapy, Epithelial Cells, Ganciclovir, Humans, Injections, Intralesional, Medulloblastoma, Mice, Neoplasm Recurrence, Local, Neural Stem Cells, Prodrugs, Skin, Surgery, Computer-Assisted, Survival Analysis, Thymidine Kinase
  • Digital Object Identifier (doi)

    Author List

  • Okolie O; Irvin DM; Bago JR; Sheets K; Satterlee A; Carey-Ewend AG; Lettry V; Dumitru R; Elton S; Ewend MG
  • Start Page

  • e0198596
  • Volume

  • 13
  • Issue

  • 7