Enhanced antitumor efficacy of vasculostatin (Vstat120) expressing oncolytic HSV-1

Jayson Hardcastle, Kazuhiko Kurozumi, Nina Dmitrieva, Martin P. Sayers, Sarwat Ahmad, Peter Waterman, Ralph Weissleder, E. Antonio Chiocca, Balveen Kaur

Research output: Contribution to journalArticle

57 Citations (Scopus)

Abstract

Oncolytic viral (OV) therapy is a promising therapeutic modality for brain tumors. Vasculostatin (Vstat120) is the cleaved and secreted extracellular fragment of brain-specific angiogenesis inhibitor 1 (BAI1), a brain-specific receptor. To date, the therapeutic efficacy of Vstat120 delivery into established tumors has not been investigated. Here we tested the therapeutic efficacy of combining Vstat120 gene delivery in conjunction with OV therapy. We constructed RAMBO (Rapid Antiangiogenesis Mediated By Oncolytic virus), which expresses Vstat120 under the control of the herpes simplex virus (HSV) IE4/5 promoter. Secreted Vstat120 was detected as soon as 4 hours postinfection in vitro and was retained for up to 13 days after OV therapy in subcutaneous tumors. RAMBO-produced Vstat120 efficiently inhibited endothelial cell migration and tube formation in vitro (P = 0.0005 and P = 0.0184, respectively) and inhibited angiogenesis (P = 0.007) in vivo. There was a significant suppression of intracranial and subcutaneous glioma growth in mice treated with RAMBO compared to the control virus, HSVQ (P = 0.0021 and P 0.05, respectively). Statistically significant reduction in tumor vascular volume fraction (VVF) and microvessel density (MVD) was observed in tumors treated with RAMBO. This is the first study to report the antitumor effects of Vstat120 delivery into established tumors and supports the further development of RAMBO as a possible cancer therapy.

Original languageEnglish
Pages (from-to)285-294
Number of pages10
JournalMolecular Therapy
Volume18
Issue number2
DOIs
Publication statusPublished - Feb 2010
Externally publishedYes

Fingerprint

Oncolytic Viruses
Human Herpesvirus 1
Neoplasms
Therapeutics
Angiogenesis Inhibitors
Brain
Simplexvirus
Microvessels
Tumor Burden
Brain Neoplasms
Glioma
Cell Movement
Blood Vessels
Endothelial Cells
Viruses
Growth

ASJC Scopus subject areas

  • Molecular Biology
  • Molecular Medicine
  • Genetics
  • Drug Discovery
  • Pharmacology

Cite this

Hardcastle, J., Kurozumi, K., Dmitrieva, N., Sayers, M. P., Ahmad, S., Waterman, P., ... Kaur, B. (2010). Enhanced antitumor efficacy of vasculostatin (Vstat120) expressing oncolytic HSV-1. Molecular Therapy, 18(2), 285-294. https://doi.org/10.1038/mt.2009.232

Enhanced antitumor efficacy of vasculostatin (Vstat120) expressing oncolytic HSV-1. / Hardcastle, Jayson; Kurozumi, Kazuhiko; Dmitrieva, Nina; Sayers, Martin P.; Ahmad, Sarwat; Waterman, Peter; Weissleder, Ralph; Chiocca, E. Antonio; Kaur, Balveen.

In: Molecular Therapy, Vol. 18, No. 2, 02.2010, p. 285-294.

Research output: Contribution to journalArticle

Hardcastle, J, Kurozumi, K, Dmitrieva, N, Sayers, MP, Ahmad, S, Waterman, P, Weissleder, R, Chiocca, EA & Kaur, B 2010, 'Enhanced antitumor efficacy of vasculostatin (Vstat120) expressing oncolytic HSV-1', Molecular Therapy, vol. 18, no. 2, pp. 285-294. https://doi.org/10.1038/mt.2009.232
Hardcastle, Jayson ; Kurozumi, Kazuhiko ; Dmitrieva, Nina ; Sayers, Martin P. ; Ahmad, Sarwat ; Waterman, Peter ; Weissleder, Ralph ; Chiocca, E. Antonio ; Kaur, Balveen. / Enhanced antitumor efficacy of vasculostatin (Vstat120) expressing oncolytic HSV-1. In: Molecular Therapy. 2010 ; Vol. 18, No. 2. pp. 285-294.
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