A novel vaccinia virus with dual oncolytic and anti-angiogenic therapeutic effects against triple-negative breast cancer

Gholami, Sepideh, Marano, Andrew, Chen, Nanhai G, Aguilar, Richard J, Frentzen, Alexa, Chen, Chun-Hao, Lou, Emil, Fujisawa, Sho, Eveno, Clarisse, Belin, Laurence, Zanzonico, Pat, Szalay, Aladar, Fong, Yuman (December 2014) A novel vaccinia virus with dual oncolytic and anti-angiogenic therapeutic effects against triple-negative breast cancer. Breast Cancer Research and Treatment, 148 (3). pp. 489-499. ISSN 0167-6806

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Abstract

Vascular endothelial growth factor (VEGF) expression is higher in triple-negative breast cancers (TNBC) compared to other subtypes and is reported to predict incidence of distant metastases and shorter overall survival. We investigated the therapeutic impact of a vaccinia virus (VACV) GLV-1h164 (derived from its parent virus GLV-1h100), encoding a single-chain antibody (scAb) against VEGF (GLAF-2) in an orthotopic TNBC murine model. GLV-1h164 was tested against multiple TNBC cell lines. Viral infectivity, cytotoxicity, and replication were determined. Mammary fat pad tumors were generated in athymic nude mice using MDA-MB-231 cells. Xenografts were treated with GLV-1h164, GLV-1h100, or PBS and followed for tumor growth. Viral infectivity was time- and concentration-dependent. GLV-1h164 killed TNBC cell lines in a dose-dependent fashion with greater than 90% cytotoxicity within 4 days at a multiplicity of infection of 5.0. In vitro, cytotoxicity of GLV-1h164 was identical to GLV-1h100. GLV-1h164 replicated efficiently in all cell lines with an over 400-fold increase in copy numbers from the initial viral dose within 4 days. In vivo, mean tumor volumes after 2 weeks of treatment were 73, 191, and 422 mm(3) (GLV-1h164, GLV-1h100, and PBS, respectively) (p < 0.05). Both in vivo Doppler ultrasonography and immuno-staining showed decreased neo-angiogenesis in GLV-1h164-treated tumors compared to both GLV-1h100 and PBS controls (p < 0.05). This is the first study to demonstrate efficient combination of oncolytic and anti-angiogenic activity of a novel VACV on TNBC xenografts. Our results suggest that GLV-1h164 is a promising therapeutic agent that warrants testing for patients with TNBC.

Item Type:	Paper
Subjects:	therapies diseases & disorders > cancer > cancer types > breast cancer therapies > viral vectors
CSHL Authors:	Gholami, Sepideh
Communities:	CSHL labs > Gholami Lab
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	December 2014
Date Deposited:	05 Oct 2023 19:30
Last Modified:	05 Oct 2023 19:30
PMCID:	PMC5724036
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/41148

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