Spectrum-Wide Exploration of Human Adenoviruses for Breast Cancer Therapy
Nicolas Mach1, Jian Gao1, Lukas Schaffarczyk1
1Virology and Microbiology, Center for Biomedical Education and Research (ZBAF), Department of Human Medicine, Faculty of Health, Witten/Herdecke University, 58453 Witten, Germany.
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.
Insights
Researchers screened various adenoviruses (Ads) for breast cancer virotherapy. Certain Ad types, like Ad3, Ad35, Ad37, and Ad52, showed high potential for targeting tumor cells, offering new therapeutic options.
Area of Science:
- Oncolytic virotherapy
- Cancer therapeutics
- Adenovirus research
Background:
- Oncolytic adenoviruses (Ads) show promise for cancer treatment, but Ad type 5 (Ad5) efficacy is limited by low coxsackievirus and adenovirus receptor (CAR) expression on tumors.
- Effective cancer virotherapy requires efficient tumor cell transduction, necessitating screening of diverse viral agents.
Purpose of the Study:
- To evaluate the transduction efficiencies of a novel human adenovirus library in breast cancer cell lines.
- To identify alternative adenovirus serotypes with high efficacy for breast cancer virotherapy.
Main Methods:
- Screened over 20 adenovirus types per cell line using high-throughput reporter assays across four breast cancer cell lines.
- Investigated transduction efficiency, transgene-positive cell percentage, and cellular entry for promising candidates.
- Performed oncolytic assays to assess tumor cell lysis efficacy of selected adenoviruses.
Main Results:
- Breast cancer cell lines exhibited low CAR expression but expressed alternative receptors like CD46, DSG-2, and integrins.
- Adenovirus types Ad3, Ad35, Ad37, and Ad52 demonstrated high transduction efficiencies and oncolytic potential.
- These identified adenoviruses represent promising candidates for breast cancer virotherapy.
Conclusions:
- Alternative adenovirus serotypes can overcome CAR-dependent limitations in breast cancer virotherapy.
- Ad3, Ad35, Ad37, and Ad52 are identified as superior candidates for developing effective breast cancer oncolytic adenovirus therapies.
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