title: Therapeutic targeting of subdural medulloblastomas using human neural stem cells expressing carboxylesterase.
abstract: The prognosis of medulloblastoma has improved significantly because of advances in multi-modal treatments; however, metastasis remains one of the prognostic factors for a poor outcome and is usually associated with tumor recurrence. We evaluated the migratory potential and therapeutic efficacy of genetically engineered human neural stem cells (NSCs) that encode a prodrug enzyme in the subdural medulloblastoma model. We genetically modified HB1.F3 (F3) immortalized human NSCs to express rabbit carboxylesterase (rCE) enzyme, which efficiently converts the prodrug CPT-11 (Irinotecan) into an active anti-cancer agent (SN-38). To simulate clinical metastatic medulloblastomas, we implanted human medulloblastoma cells into the subdural spaces of nude mice. rCE expressing NSCs (F3.rCE) were labeled with fluorescence magnetic nanoparticle for in vivo imaging. The therapeutic potential of F3.rCE was confirmed using a mouse subdural medulloblastoma model. The majority of intravenously (i.v.) injected, F3.rCE cells migrated to the subdural medulloblastoma site and a small number of F3.rCE cells were found in the lungs, pancreas, kidney and liver. Animals that received F3.rCE cells in combination with prodrug CPT-11 survived significantly longer (median survival: 142 days) than control mice that received F3.rCE cells only (median survival: 80 days, P<0.001) or CPT-11 only (median survival: 118 days, P<0.001). In conclusion, i.v. injected F3.rCE NSCs were able to target subdural medulloblastomas and demonstrate therapeutic efficacy. Our study provides data that supports further investigation of stem-cell-based gene therapy against metastatic medulloblastomas.
authors.affiliation: Department of Neurosurgery, Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, Seoul National University College of Medicine, Korea.
authors.forename: S-H
authors.initials: SH
authors.lastname: Lim
authors.forename: S A
authors.initials: SA
authors.lastname: Choi
authors.forename: J Y
authors.initials: JY
authors.lastname: Lee
authors.forename: K-C
authors.initials: KC
authors.lastname: Wang
authors.forename: J H
authors.initials: JH
authors.lastname: Phi
authors.forename: D-H
authors.initials: DH
authors.lastname: Lee
authors.forename: S H
authors.initials: SH
authors.lastname: Song
authors.forename: J H
authors.initials: JH
authors.lastname: Song
authors.forename: X
authors.initials: X
authors.lastname: Jin
authors.forename: H
authors.initials: H
authors.lastname: Kim
authors.forename: H J
authors.initials: HJ
authors.lastname: Lee
authors.forename: I
authors.initials: I
authors.lastname: Lim
authors.forename: S U
authors.initials: SU
authors.lastname: Kim
authors.forename: S-K
authors.initials: SK
authors.lastname: Kim
mesh_terms: D000818:Animals; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D043182:Carboxylesterase / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D002528:Cerebellar Neoplasms / Q000201:enzymology / Q000235:genetics / Q000601:surgery / Q000628:therapy*; D015316:Genetic Therapy; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008527:Medulloblastoma / Q000201:enzymology / Q000235:genetics / Q000601:surgery / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D058953:Neural Stem Cells / Q000201:enzymology / Q000502:physiology* / Q000637:transplantation*; D011379:Prognosis; D011817:Rabbits; D011897:Random Allocation; D023041:Xenograft Model Antitumor Assays
chemical_list: D000077146:Irinotecan; D043182:Carboxylesterase; D002166:Camptothecin