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Therapeutic targeting of subdural medulloblastomas using human neural stem cells expressing carboxylesterase

Cancer Gene Therapy volume 18, pages 817–824 (2011)Cite this article

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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.

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Acknowledgements

This study was supported by grants from the National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (08203103_22650) by the National Research Foundation of Korea (NRF) grant and funded by the Korea government (MEST) (2008-0061821). We thank CJ Cheiljedang for providing CPT-11.

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  1. S-H Lim and S A Choi: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neurosurgery, Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Korea

    S-H Lim, S A Choi, J Y Lee, K-C Wang, J H Phi, D-H Lee & S-K Kim

  2. Department of Laboratory Medicine, Seoul National University Bundang Hospital, Songnam, Korea

    S H Song & J H Song

  3. Department of Life Sciences, Cell Growth Regulation Laboratory, School of Life Sciences and Biotechnology, Korea University, Seoul, Korea

    X Jin & H Kim

  4. Department of Applied Chemistry, Medical Research Institute, Chung-Ang University College of Medicine, Seoul, Korea

    H J Lee & S U Kim

  5. Division of Neurology, Department of Medicine, UBC Hospital, University of British Columbia, Vancouver, British Columbia, Canada

    H J Lee & S U Kim

  6. Department of Physiology, Chung-Ang University College of Medicine, Seoul, Korea

    I Lim

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  1. S-H Lim
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Correspondence to S U Kim or S-K Kim.

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Lim, SH., Choi, S., Lee, J. et al. Therapeutic targeting of subdural medulloblastomas using human neural stem cells expressing carboxylesterase. Cancer Gene Ther 18, 817–824 (2011). https://doi.org/10.1038/cgt.2011.52

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  • DOI: https://doi.org/10.1038/cgt.2011.52

Keywords

  • medulloblastoma
  • metastasis
  • neural stem cell
  • tumor tropism
  • gene-directed enzyme prodrug therapy
  • carboxylesterase

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