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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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References

  1. Packer RJ, Sutton LN, Elterman R, Lange B, Goldwein J, Nicholson HS et al. Outcome for children with medulloblastoma treated with radiation and cisplatin, CCNU, and vincristine chemotherapy. J Neurosurg 1994; 81: 690–698.

    Article  CAS  PubMed  Google Scholar 

  2. David KM, Casey AT, Hayward RD, Harkness WF, Phipps K, Wade A . Medulloblastoma: is the 5-year survival rate improving? A review of 80 cases from a single institution. J Neurosurg 1997; 86: 13–21.

    Article  CAS  PubMed  Google Scholar 

  3. Habrand JL, De Crevoisier R . Radiation therapy in the management of childhood brain tumors. Childs NervSyst 2001; 17: 121–133.

    Article  CAS  Google Scholar 

  4. Patrice SJ, Tarbell NJ, Goumnerova LC, Shrieve DC, Black PM, Loeffler JS . Results of radiosurgery in the management of recurrent and residual medulloblastoma. Pediatr Neurosurg 1995; 22: 197–203.

    Article  CAS  PubMed  Google Scholar 

  5. Graham ML, Herndon JEII, Casey JR . High-dose chemotherapy with autologous stem-cell rescue in patients with recurrent and high-risk pediatric brain tumors. J Clin Oncol 1997; 15: 1814–1823.

    Article  CAS  PubMed  Google Scholar 

  6. Mulhern RK, Palmer SL, Merchant TE, Wallace D, Kocak M, Brouwers P et al. Neurocognitive consequences of risk-adapted therapy for childhood medulloblastoma. J Clin Oncol 2005; 23: 5511–5519.

    Article  PubMed  Google Scholar 

  7. Chang DY, Yoo SW, Hong Y, Kim S, Kim SJ, Yoon SH et al. The growth of brain tumors can be suppressed by multiple transplantation of mesenchymal stem cells expressing cytosine deaminase. Int J Cancer 2010; 127: 1975–1983.

    Article  CAS  PubMed  Google Scholar 

  8. Shimato S, Natsume A, Takeuchi H, Wakabayashi T, Fujii M, Ito M et al. Human neural stem cells target and deliver therapeutic gene to experimental leptomeningeal medulloblastoma. Gene Ther 2007; 14: 1132–1142.

    Article  CAS  PubMed  Google Scholar 

  9. Kim SK, Cargioli TG, Machluf M, Yang W, Sun Y, A-Hashem R et al. PEX-producing human neural stem cells inhibit tumor growth in a mouse glioma model. Clin Cancer Res 2005; 11: 5965–5970.

    Article  CAS  PubMed  Google Scholar 

  10. Aboody KS, Bush RA, Garcia E, Metz MZ, Najbauer J, Justus KA et al. Development of a tumor-selective approach to treat metastatic cancer. PLoS ONE 2006; 1: 1–10.

    Article  Google Scholar 

  11. Joo KM, Park IH, Shin JY, Jin J, Kang BG, Kim MH et al. Human neural stem cells can target and deliver therapeutic genes to breast cancer brain metastases. Mol Ther 2009; 17: 570–575.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Danks MK, Yoon KJ, Bush RA, Remack JS, Wierdl M, Kim SU et al. Tumor-targeted enzyme/prodrug therapy mediates long-term disease-free survival of mice bearing disseminated neuroblastoma. Cancer Res 2007; 67: 22–25.

    Article  CAS  PubMed  Google Scholar 

  13. Dachs GU, Tupper J, Tozer GM . From bench to bedside for gene-directed enzyme prodrug therapy of cancer. Anticancer Drugs 2005; 16: 349–359.

    Article  CAS  PubMed  Google Scholar 

  14. McGregor LM, Spunt SL, Furman WL, Stewart CF, Schaiquevich P, Krailo MD et al. Phase 1 study of oxaliplatin and irinotecan in pediatric patients with refractory solid tumors: a children′s oncology group study. Cancer 2009; 115: 1765–1775.

    Article  PubMed  Google Scholar 

  15. Tanizawa A, Fujimori A, Fujimori Y, Pommier Y . Comparison of topoisomerase I inhibition, DNA damage, and cytotoxicity of camptothecin derivatives presently in clinical trials. J Natl Cancer Inst 1994; 86: 836–842.

    Article  CAS  PubMed  Google Scholar 

  16. Guemei AA, Cottrell J, Band R, Hehman H, Prudhomme M, Pavlov MV et al. Human plasma carboxylesterase and butyrylcholinesterase enzyme activity: correlations with SN-38 pharmacokinetics during a prolonged infusion of irinotecan. Cancer Chemother Pharmacol 2001; 47: 283–290.

    Article  CAS  PubMed  Google Scholar 

  17. Danks MK, Morton CL, Krull EJ, Cheshire PJ, Richmond LB, Naeve CW et al. Comparison of activation of CPT-11 by rabbit and human carboxylesterases for use in enzyme/prodrug therapy. Clin Cancer Res 1999; 5: 917–924.

    CAS  PubMed  Google Scholar 

  18. Wagner LM, Guichard SM, Burger RA, Morton CL, Straign CM, Ashmun RA et al. Efficacy and toxicity of a virusdirected enzyme prodrug therapy purging method: preclinical assessment and application to bone marrow samples from neuroblastoma patients. Cancer Res 2002; 62: 5001–5007.

    CAS  PubMed  Google Scholar 

  19. Wierdl M, Morton CL, Weeks JK, Danks MK, Harris LC, Potter PM . Sensitization of human tumor cells to CPT-11 via adenoviral-mediated delivery of a rabbit liver carboxylesterase. Cancer Res 2001; 61: 5078–5082.

    CAS  PubMed  Google Scholar 

  20. Lee HJ, Kim KS, Kim EJ, Choi HB, Lee KH, Park IH et al. Brain transplantation of immortalized human neural stem cells promotes functional recovery in mouse intracerebral hemorrhage stroke model. Stem Cells 2007; 25: 1204–1212.

    Article  CAS  PubMed  Google Scholar 

  21. Kim SU, Nagai A, Nakagawa E, Choi HB, Bang JH, Lee HJ et al. Production and characterization of immortal human neural stem cell line with multipotent differentiation property. Methods Mol Biol 2008; 438: 103–121.

    Article  CAS  PubMed  Google Scholar 

  22. Kim SU, de Vellis J . Stem cell-based cell therapy in neurological diseases: a review. J Neurosci Res 2009; 87: 2183–2200.

    Article  CAS  PubMed  Google Scholar 

  23. Cargioli TG, Ugur HC, Ramakrishna N, Chan J, Black PM, Carroll RS . Establishment of an in vivo meningioma model with human telomerase reverse transcriptase. Neurosurgery 2007; 60: 750–759.

    Article  PubMed  Google Scholar 

  24. Schmidt KF, Ziu M, Schmidt NO, Vaghasia P, Cargioli TG, Doshi S et al. Volume reconstruction techniques improve the correlation between histological and in vivo tumor volume measurements in mouse models of human gliomas. J Neurooncol 2004; 68: 207–215.

    Article  PubMed  Google Scholar 

  25. Yin J, Kim JK, Moon JH, Beck S, Piao D, Jin X et al. hMSC-mediated concurrent delivery of endostatin and carboxylesterase to mouse xenografts suppresses glioma initiation and recurrence. Mol Ther 2011; 19: 1161–1169.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Gutierrez AA, Lemoine NR, Sikora K . Gene therapy for cancer. Lancet 1992; 339: 715–721.

    Article  CAS  PubMed  Google Scholar 

  27. Moolten FL . Drug sensitivity (‘suicide’) genes for selective cancer chemotherapy. Cancer Gene Ther 1994; 1: 279–287.

    CAS  PubMed  Google Scholar 

  28. Wierdl M, Tsurkan L, Hyatt JL, Edwards CC, Hatfield MJ, Morton CL et al. An improved human carboxylesterase for enzyme/prodrug therapy with CPT-11. Cancer Gene Ther 2008; 15: 183–192.

    Article  CAS  PubMed  Google Scholar 

  29. Jurvansuu J, Zhao Y, Leung DS, Boulaire J, Yu YH, Ahmed S et al. Transmembrane protein 18 enhances the tropism of neural stem cells for glioma cells. Cancer Res 2008; 68: 4614–4622.

    Article  CAS  PubMed  Google Scholar 

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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

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