Spectrum-Wide Exploration of Human Adenoviruses for Breast Cancer Therapy.

Nicolas Mach,Sebastian Janz,Thomas Dittmar,Eric Ehrke-Schulz,Jian Gao,Anja Ehrhardt,Wenli Zhang,Lukas Schaffarczyk

doi:10.3390/cancers12061403

Abstract

Oncolytic adenoviruses (Ads) are promising tools for cancer therapeutics. However, most Ad-based therapies utilize Ad type 5 (Ad5), which displays unsatisfying efficiency in clinical trials, partly due to the low expression levels of its primary coxsackievirus and adenovirus receptor (CAR) on tumor cells. Since the efficacy of virotherapy strongly relies on efficient transduction of targeted tumor cells, initial screening of a broad range of viral agents to identify the most effective vehicles is essential. Using a novel Ad library consisting of numerous human Ads representing known Ad species, we evaluated the transduction efficiencies in four breast cancer (BC) cell lines. For each cell line over 20 Ad types were screened in a high-throughput manner based on reporter assays. Ad types featuring high transduction efficiencies were further investigated with respect to the percentage of transgene-positive cells and efficiencies of cellular entry in individual cell lines. Additionally, oncolytic assay was performed to test tumor cell lysis efficacy of selected Ad types. We found that all analyzed BC cell lines show low expression levels of CAR, while alternative receptors such as CD46, DSG-2, and integrins were also detected. We identified Ad3, Ad35, Ad37, and Ad52 as potential candidates for BC virotherapy.

Highlights

Cancer is the second leading cause of death in industrialized countries and constitutes an enormous burden on the health-care system
We investigated whether modestly transducing the breast epithelial cell line M13SV1
We investigated whether transduction efficiencies of Ads correlate with specific features of the breast cancer (BC) type such as grading and transduction efficiencies of Ads correlate with specific features of the BC type such as grading and receptor expression and which Ad types induce efficient tumor cell lysis

Summary

Introduction

Cancer is the second leading cause of death in industrialized countries and constitutes an enormous burden on the health-care system. Breast cancer (BC) is the most commonly diagnosed cancer (24.2%) and the leading cause of cancer deaths (11.6%) in women worldwide [1]. Treatment options of BC patients depend on the grading and specific features of the BC type. Hormone receptor-positive (estrogen receptors, ER+; progesterone receptors, PR+) BC can be treated with hormone-blocking agents comprising selective estrogen receptor modulators or aromatase inhibitors. Estrogen receptor-negative (ER−) BC are primarily treated with radiochemotherapy targeting fast-replicating cancer cells [2]. Chemotherapy causes damage to physiologic, fast-growing cells. Since 25–30% of BCs overexpress the human epidermal growth factor receptor

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