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Neural stem cell-mediated CE/CPT-11 enzyme/prodrug therapy in transgenic mouse model of intracerebellar medulloblastoma

Gene Therapy volume 20, pages 143–150 (2013)Cite this article

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Abstract

Medulloblastoma is a heterogeneous diffuse neoplasm that can be highly disseminated, and is the most common malignant childhood brain tumor. Although multimodal treatments have improved survival rates for patients with medulloblastoma, these tumors are associated with high morbidity and mortality. New treatment strategies are urgently needed to improve cure rates and, importantly, to spare normal brain tissue from neurotoxicity and patients from life-long cognitive and functional deficits associated with current therapies. In numerous preclinical brain tumor models, neural stem cells (NSCs) have shown great promise as delivery vehicles for therapeutic genes. Here, we have used an established, genetically modified human NSC line (HB1.F3.CD) to deliver carboxylesterase (CE) to cerebellar tumor foci and locally activate the prodrug camptothecin-11 (CPT-11) (Irinotecan) to the potent topoisomerase I inhibitor SN-38. HB1.F3.CD NSC tumor tropism, intratumoral distribution and therapeutic efficacy were investigated in clinically relevant experimental models. Magnetic resonance imaging was used for in vivo tracking of iron nanoparticle-labeled NSCs, and to assess the therapeutic efficacy of CE-expressing HB1.F3.CD cells. As compared with controls, a significant decrease in tumor growth rate was seen in mice that received both NSCs and CPT-11 as their treatment regimen. Thus, this study provides proof-of-concept for NSC-mediated CE/CPT-11 treatment of medulloblastoma, and serves as a foundation for further studies toward potential clinical application.

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Acknowledgements

We are grateful to Dr Keely L Walker (City of Hope) for critical reading and editing of the manuscript. We also thank Dr Rolando F Del Maestro (McGill University, Montreal, Canada) for providing the UW228 primary medulloblastoma cell line. We are grateful to the USC/CHLA Small Animal Imaging Core for assistance with animal studies and MR imaging, and Dr Philip Potter (St Jude Children's Research Hospital, Memphis, TN) for providing the rCE adenoviral vector. This work was supported with funds from the ThinkCure Foundation, California Institute of Regernerative Medicine DR1-01421, The Jean Perkins Foundation, The TJ Martell Foundation, the Rosalinde and Arthur Gilbert Foundation, the National Cancer Institute (Grant number P30 CA33572) and the Stop Cancer Foundation.

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Author notes

  1. R A Moats and K S Aboody: The laboratories of KS Aboody and RA Moats contributed equally to this work as part of a City of Hope—Children's Hospital of Los Angeles research collaboration.

Authors and Affiliations

  1. Department of Neurosciences, Beckman Research Institute of the City of Hope, Duarte, CA, USA

    M Gutova, K A Herrmann, Y Abramyants, A J Annala, J Najbauer, M E Barish & K S Aboody

  2. Division of Hematology-Oncology, USC Keck School of Medicine, The Saban Research Institute of Children's Hospital Los Angeles, Los Angeles, CA, USA

    G M Shackleford, X-H Shi & K Mittelholtz

  3. Department of Radiology, USC Keck School of Medicine, The Saban Research Institute of Children's Hospital Los Angeles, Los Angeles, CA, USA

    G M Shackleford, V Khankaldyyan & R A Moats

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

    X-H Shi

  5. Division of Information Sciences, Beckman Research Institute of the City of Hope, Duarte, CA, USA

    M S Blanchard

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

    S U Kim

  7. Division of Clinical and Molecular Pharmacology, Beckman Research Institute of the City of Hope, Duarte, CA, USA

    T W Synold

  8. Department of Pathology, Beckman Research Institute of the City of Hope, Duarte, CA, USA

    M D'Apuzzo

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  1. M Gutova
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Correspondence to M Gutova or R A Moats.

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Competing interests

KSA, AJA are founders, CSO and COO (respectively) of TheraBiologics, Inc., a clinical stage biopharmaceutical company supporting development of NSC-mediated cancer treatments. The remaining authors declare no conflict of interest.

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Gutova, M., Shackleford, G., Khankaldyyan, V. et al. Neural stem cell-mediated CE/CPT-11 enzyme/prodrug therapy in transgenic mouse model of intracerebellar medulloblastoma. Gene Ther 20, 143–150 (2013). https://doi.org/10.1038/gt.2012.12

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