TY - JOUR
T1 - Enhancing antitumor efficacy of heavily vascularized tumors by rambo virus through decreased tumor endothelial cell activation
AU - Nair, Mitra
AU - Khosla, Maninder
AU - Otani, Yoshihiro
AU - Yeh, Margaret
AU - Park, Flora
AU - Shimizu, Toshihiko
AU - Kang, Jin Muk
AU - Bolyard, Chelsea
AU - Yu, Jun Ge
AU - Banasavadi-Siddegowda, Yeshavanth Kumar
AU - Lopez, Gonzalo
AU - Kaur, Balveen
AU - Pollock, Raphael E.
AU - Lee, Tae Jin
AU - Old, Matthew
AU - Yoo, Ji Young
N1 - Funding Information:
Funding: This work was supported by Research Scholar Grants (RSG-19-185-01-MPC) from the American Cancer Society to J.Y.Y, by National Institute of Health (NIH) grants R01 NS064607, P01CA163205, R01 CA150153 to B.K, and by The Ohio State University Comprehensive Cancer Center (OSUCCC) and the NIH P30 CA016058) to R.S. and R.E.P.
Funding Information:
This work was supported by Research Scholar Grants (RSG-19-185-01-MPC) from the American Cancer Society to J.Y.Y, by National Institute of Health (NIH) grants R01 NS064607, P01CA163205, R01 CA150153 to B.K, and by The Ohio State University Comprehensive Cancer Center (OSUCCC) and the NIH P30 CA016058) to R.S. and R.E.P.
Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2020/4
Y1 - 2020/4
N2 - Vascularization is a common pathology for many solid tumors, and therefore anti-angiogenic strategies are being investigated as a therapeutic target for treatment. Numerous studies are also being conducted regarding the effects of oncolytic viruses, including Imlygic™, an FDA approved oncolytic herpes simplex virus-1 (oHSV) for the treatment of highly vascularized tumors such as Kaposi sarcoma (NCT04065152), and brain tumors. To our knowledge, the effects of combining oncolytic HSV with angiogenesis inhibition on endothelial cell activation has not been previously described. Here, we tested the effects of Rapid Antiangiogenesis Mediated By Oncolytic Virus (RAMBO), an oHSV which expresses a potent anti-angiogenic gene Vasculostatin on endothelial cell activation in heavily vascularized solid tumors. oHSV treatment induces endothelial cell activation, which inhibits virus propagation and oncolysis in adjacent tumor cells in vitro. Consistently, this was also observed in intravital imaging of intracranial tumor-bearing mice in vivo where infected tumor endothelial cells could efficiently clear the virus without cell lysis. Quantitative real-time PCR (Q-PCR), leukocyte adhesion assay, and fluorescent microscopy imaging data, however, revealed that RAMBO virus significantly decreased expression of endothelial cell activation markers and leukocyte adhesion, which in turn increased virus replication and cytotoxicity in endothelial cells. In vivo RAMBO treatment of subcutaneously implanted sarcoma tumors significantly reduced tumor growth in mice bearing sarcoma compared to rHSVQ. In addition, histological analysis of RAMBO-treated tumor tissues revealed large areas of necrosis and a statistically significant reduction in microvessel density (MVD). This study provides strong preclinical evidence of the therapeutic benefit for the use of RAMBO virus as a treatment option for highly vascularized tumors.
AB - Vascularization is a common pathology for many solid tumors, and therefore anti-angiogenic strategies are being investigated as a therapeutic target for treatment. Numerous studies are also being conducted regarding the effects of oncolytic viruses, including Imlygic™, an FDA approved oncolytic herpes simplex virus-1 (oHSV) for the treatment of highly vascularized tumors such as Kaposi sarcoma (NCT04065152), and brain tumors. To our knowledge, the effects of combining oncolytic HSV with angiogenesis inhibition on endothelial cell activation has not been previously described. Here, we tested the effects of Rapid Antiangiogenesis Mediated By Oncolytic Virus (RAMBO), an oHSV which expresses a potent anti-angiogenic gene Vasculostatin on endothelial cell activation in heavily vascularized solid tumors. oHSV treatment induces endothelial cell activation, which inhibits virus propagation and oncolysis in adjacent tumor cells in vitro. Consistently, this was also observed in intravital imaging of intracranial tumor-bearing mice in vivo where infected tumor endothelial cells could efficiently clear the virus without cell lysis. Quantitative real-time PCR (Q-PCR), leukocyte adhesion assay, and fluorescent microscopy imaging data, however, revealed that RAMBO virus significantly decreased expression of endothelial cell activation markers and leukocyte adhesion, which in turn increased virus replication and cytotoxicity in endothelial cells. In vivo RAMBO treatment of subcutaneously implanted sarcoma tumors significantly reduced tumor growth in mice bearing sarcoma compared to rHSVQ. In addition, histological analysis of RAMBO-treated tumor tissues revealed large areas of necrosis and a statistically significant reduction in microvessel density (MVD). This study provides strong preclinical evidence of the therapeutic benefit for the use of RAMBO virus as a treatment option for highly vascularized tumors.
KW - Angiogenesis
KW - Oncolytic herpes simplex virus-1 (oHSV)
KW - Rapid antiangiogenesis mediated by oncolytic virus (RAMBO)
KW - Soft tissue sarcoma (STS)
KW - Tumor microenvironment (TME)
KW - Vasculostatin (Vstat120)
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U2 - 10.3390/cancers12041040
DO - 10.3390/cancers12041040
M3 - Article
AN - SCOPUS:85083829480
SN - 2072-6694
VL - 12
JO - Cancers
JF - Cancers
IS - 4
M1 - 1040
ER -