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

doi:10.1038/mt.2009.232

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 journal › Article › peer-review

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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 language	English (US)
Pages (from-to)	285-294
Number of pages	10
Journal	Molecular Therapy
Volume	18
Issue number	2
DOIs	https://doi.org/10.1038/mt.2009.232
State	Published - Feb 2010
Externally published	Yes

ASJC Scopus subject areas

Molecular Medicine
Molecular Biology
Genetics
Pharmacology
Drug Discovery

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/mt.2009.232

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@article{0b8f42ee875042de98d50fcfcef52125,

title = "Enhanced antitumor efficacy of vasculostatin (Vstat120) expressing oncolytic HSV-1",

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.",

author = "Jayson Hardcastle and Kazuhiko Kurozumi and Nina Dmitrieva and Sayers, {Martin P.} and Sarwat Ahmad and Peter Waterman and Ralph Weissleder and Chiocca, {E. Antonio} and Balveen Kaur",

note = "Funding Information: This work was supported by funding from the National Institutes of Health grant (1K01NS059575, R01NS064607, and R21NS056203 to B.K.; P01 CA069246 to E.A.C. and R.W.; and R24 CA92782 to R.W.); American Association for Neurological Surgeons/Congress of Neurological Surgeons, Section on Tumors/BrainLAB International Research Fellowship (to K.K.); American Brain Tumor Association medical student summer fellowship (to S.A.); and the Alex Lemonade Stand Foundation young investigator award (to B.K.).",

year = "2010",

month = feb,

doi = "10.1038/mt.2009.232",

language = "English (US)",

volume = "18",

pages = "285--294",

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T1 - Enhanced antitumor efficacy of vasculostatin (Vstat120) expressing oncolytic HSV-1

AU - Hardcastle, Jayson

AU - Kurozumi, Kazuhiko

AU - Dmitrieva, Nina

AU - Sayers, Martin P.

AU - Ahmad, Sarwat

AU - Waterman, Peter

AU - Weissleder, Ralph

AU - Chiocca, E. Antonio

AU - Kaur, Balveen

N1 - Funding Information: This work was supported by funding from the National Institutes of Health grant (1K01NS059575, R01NS064607, and R21NS056203 to B.K.; P01 CA069246 to E.A.C. and R.W.; and R24 CA92782 to R.W.); American Association for Neurological Surgeons/Congress of Neurological Surgeons, Section on Tumors/BrainLAB International Research Fellowship (to K.K.); American Brain Tumor Association medical student summer fellowship (to S.A.); and the Alex Lemonade Stand Foundation young investigator award (to B.K.).

PY - 2010/2

Y1 - 2010/2

N2 - 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.

AB - 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.

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

Abstract

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