Oncotarget

Research Papers:

Oncolytic reovirus inhibits angiogenesis through induction of CXCL10/IP-10 and abrogation of HIF activity in soft tissue sarcomas

Jennifer S. Carew, Claudia M. Espitia, Weiguo Zhao, Monica M. Mita, Alain C. Mita and Steffan T. Nawrocki _

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Oncotarget. 2017; 8:86769-86783. https://doi.org/10.18632/oncotarget.21423

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Abstract

Jennifer S. Carew1, Claudia M. Espitia2, Weiguo Zhao2, Monica M. Mita3, Alain C. Mita3 and Steffan T. Nawrocki1

1University of Arizona Cancer Center and Department of Medicine, Division of Translational and Regenerative Medicine, University of Arizona, Tucson, AZ, USA

2Division of Hematology/Oncology, Cancer Therapy and Research Center at The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

3Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA

Correspondence to:

Steffan T. Nawrocki, email: [email protected]

Keywords: reovirus, CXCL10, HIF-1, angiogenesis, reolysin

Received: July 26, 2017     Accepted: August 31, 2017     Published: September 30, 2017

ABSTRACT

The tumor-selective viral replication capacity and pro-apoptotic effects of oncolytic reovirus have been reported to be dependent on the presence of an activated RAS pathway in several solid tumor types. However, the mechanisms of selective anticancer efficacy of the reovirus-based formulation for cancer therapy (Reolysin, pelareorep) have not been rigorously studied in soft tissue sarcomas (STS). Here we report that Reolysin triggered a striking induction of the anti-angiogenic chemokine interferon-γ-inducible protein 10 (IP-10)/CXCL10 (CXC chemokine ligand 10) in both wild type and RAS mutant STS cells. Further analysis determined that Reolysin treatment possessed significant anti-angiogenic activity irrespective of RAS status. In addition to CXCL10 induction, Reolysin dramatically downregulated the expression of hypoxia inducible factor (HIF)-1α, HIF-2α and inhibited vascular endothelial growth factor (VEGF) secretion. CXCL10 antagonism significantly diminished the anti-angiogenic effects of Reolysin indicating that it is a key driver of this phenomenon. Xenograft studies demonstrated that Reolysin significantly improved the anticancer activity of the anti-angiogenic agents sunitinib, temsirolimus, and bevacizumab in a manner that was associated with increased CXCL10 levels. This effect was most pronounced following treatment with Reolysin in combination with temsirolimus. Further analysis in additional sarcoma xenograft models confirmed the significant increase in CXCL10 and increased anticancer activity of this combination. Our collective results demonstrate that Reolysin possesses CXCL10-driven anti-angiogenic activity in sarcoma models, which can be harnessed to enhance the anticancer activity of temsirolimus and other agents that target the tumor vasculature.


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