Toca 511 gene transfer and 5-fluorocytosine in combination with temozolomide demonstrates synergistic therapeutic efficacy in a temozolomide-sensitive glioblastoma model

T. T. Huang, J. Hlavaty, D. Ostertag, F. L. Espinoza, B. Martin, H. Petznek, M. Rodriguez-Aguirre, C. E. Ibañez, Noriyuki Kasahara, W. Gunzburg, H. E. Gruber, D. Pertschuk, D. J. Jolly, J. M. Robbins

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Toca 511 (vocimagene amiretrorepvec), an amphotropic retroviral replicating vector (RRV), can successfully and safely deliver a functional, optimized cytosine deaminase (CD) gene to tumors in orthotopic glioma models. This agent, in conjunction with subsequent oral extended-release 5-fluorocytosine (5-FC) (Toca FC), is currently under investigation in patients with recurrent high-grade glioma. Temozolomide (TMZ) with radiation is the most frequently used first-line treatment for patients with glioblastoma, the most common and aggressive form of primary brain cancer in adults. However, subsets of patients with certain genetic alterations do not respond well to TMZ treatment and the overall median survival for patients who respond remains modest, suggesting that combinatorial approaches may be necessary to significantly improve outcomes. We show that in vitro TMZ delays but does not prevent RRV spread, nor interfere with Toca 511+5-FC-mediated cell killing in glioma tumor cells, and in vivo there is no significant hematologic effect from the combination of 5-FC and the clinically relevant dose of TMZ. A synergistic long-term survival advantage is observed in mice bearing an orthotopic TMZ-sensitive glioma after Toca 511 administration followed by coadministration of TMZ and 5-FC. These results provide support for the investigation of this novel combination treatment strategy in patients with newly diagnosed malignant glioma.

Original languageEnglish (US)
Pages (from-to)544-551
Number of pages8
JournalCancer Gene Therapy
Volume20
Issue number10
DOIs
StatePublished - Oct 2013
Externally publishedYes

Fingerprint

temozolomide
Flucytosine
Glioblastoma
Glioma
Genes
Therapeutics
Cytosine Deaminase
Survival
Brain Neoplasms
Neoplasms
Radiation

Keywords

  • Brain cancer
  • Cytosine deaminase
  • Temodar
  • Toca 511

ASJC Scopus subject areas

  • Cancer Research
  • Molecular Medicine
  • Molecular Biology

Cite this

Toca 511 gene transfer and 5-fluorocytosine in combination with temozolomide demonstrates synergistic therapeutic efficacy in a temozolomide-sensitive glioblastoma model. / Huang, T. T.; Hlavaty, J.; Ostertag, D.; Espinoza, F. L.; Martin, B.; Petznek, H.; Rodriguez-Aguirre, M.; Ibañez, C. E.; Kasahara, Noriyuki; Gunzburg, W.; Gruber, H. E.; Pertschuk, D.; Jolly, D. J.; Robbins, J. M.

In: Cancer Gene Therapy, Vol. 20, No. 10, 10.2013, p. 544-551.

Research output: Contribution to journalArticle

Huang, TT, Hlavaty, J, Ostertag, D, Espinoza, FL, Martin, B, Petznek, H, Rodriguez-Aguirre, M, Ibañez, CE, Kasahara, N, Gunzburg, W, Gruber, HE, Pertschuk, D, Jolly, DJ & Robbins, JM 2013, 'Toca 511 gene transfer and 5-fluorocytosine in combination with temozolomide demonstrates synergistic therapeutic efficacy in a temozolomide-sensitive glioblastoma model', Cancer Gene Therapy, vol. 20, no. 10, pp. 544-551. https://doi.org/10.1038/cgt.2013.51
Huang, T. T. ; Hlavaty, J. ; Ostertag, D. ; Espinoza, F. L. ; Martin, B. ; Petznek, H. ; Rodriguez-Aguirre, M. ; Ibañez, C. E. ; Kasahara, Noriyuki ; Gunzburg, W. ; Gruber, H. E. ; Pertschuk, D. ; Jolly, D. J. ; Robbins, J. M. / Toca 511 gene transfer and 5-fluorocytosine in combination with temozolomide demonstrates synergistic therapeutic efficacy in a temozolomide-sensitive glioblastoma model. In: Cancer Gene Therapy. 2013 ; Vol. 20, No. 10. pp. 544-551.
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