Treating brain tumor-initiating cells using a combination of myxoma virus and rapamycin

Franz J. Zemp, Xueqing Lun, Brienne A. McKenzie, Hongyuan Zhou, Lori Maxwell, Beichen Sun, John J.P. Kelly, Owen Stechishin, Artee Luchman, Samuel Weiss, J. Gregory Cairncross, Mark G. Hamilton, Brian A. Rabinovich, Masmudur M. Rahman, Mohamed R. Mohamed, Sherin Smallwood, Donna L. Senger, John Bell, Grant McFadden, Peter A. Forsyth

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

Background: Intratumoral heterogeneity in glioblastoma multiforme (GBM) poses a significant barrier to therapy in certain subpopulation such as the tumor-initiating cell population, being shown to be refractory to conventional therapies. Oncolytic virotherapy has the potential to target multiple compartments within the tumor and thus circumvent some of the barriers facing conventional therapies. In this study, we investigate the oncolytic potential of myxoma virus (MYXV) alone and in combination with rapamycin in vitro and in vivo using human brain tumor-initiating cells (BTICs). Methods: We cultured fresh GBM specimens as neurospheres and assayed their growth characteristics in vivo. We then tested the susceptibility of BTICs to MYXV infection with or without rapamycin in vitro and assessed viral biodistribution/survival in vivo in orthotopic xenografts. Results: The cultured neurospheres were found to retain stem cell markers in vivo, and they closely resembled human infiltrative GBM. In this study we determined that (i) all patient-derived BTICs tested, including those resistant to temozolomide, were susceptible to MYXV replication and killing in vitro; (ii) MYXV replicated within BTICs in vivo, and intratumoral administration of MYXV significantly prolonged survival of BTIC-bearing mice; (iii) combination therapy with MYXV and rapamycin improved antitumor activity, even in mice bearing "advanced" BTIC tumors; (iv) MYXV treatment decreased expression of stem cell markers in vitro and in vivo. Conclusions: Our study suggests that MYXV in combination with rapamycin infects and kills both the BTICs and the differentiated compartments of GBM and may be an effective treatment even in TMZ-resistant patients.

Original languageEnglish (US)
Pages (from-to)904-920
Number of pages17
JournalNeuro-Oncology
Volume15
Issue number7
DOIs
StatePublished - Jul 2013

Keywords

  • brain tumor initiating cells
  • malignant glioma
  • myxoma virus
  • oncolytic virus
  • rapamycin

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology
  • Cancer Research

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  • Cite this

    Zemp, F. J., Lun, X., McKenzie, B. A., Zhou, H., Maxwell, L., Sun, B., Kelly, J. J. P., Stechishin, O., Luchman, A., Weiss, S., Cairncross, J. G., Hamilton, M. G., Rabinovich, B. A., Rahman, M. M., Mohamed, M. R., Smallwood, S., Senger, D. L., Bell, J., McFadden, G., & Forsyth, P. A. (2013). Treating brain tumor-initiating cells using a combination of myxoma virus and rapamycin. Neuro-Oncology, 15(7), 904-920. https://doi.org/10.1093/neuonc/not035