Differential Susceptibility of Ex Vivo Primary Glioblastoma Tumors to Oncolytic Effect of Modified Zika Virus

Author:

Garcia Gustavo1ORCID,Chakravarty Nikhil2,Paiola Sophia1,Urena Estrella1,Gyani Priya1,Tse Christopher1,French Samuel W.34,Danielpour Moise5ORCID,Breunig Joshua J.5678,Nathanson David A.14,Arumugaswami Vaithilingaraja1910

Affiliation:

1. Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA 90095, USA

2. Department of Epidemiology, University of California Los Angeles, Los Angeles, CA 90095, USA

3. Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA

4. Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA 90095, USA

5. Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA

6. Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA

7. Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA

8. Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA

9. Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California Los Angeles, Los Angeles, CA 90095, USA

10. California NanoSystems Institute, University of California Los Angeles, Los Angeles, CA 90095, USA

Abstract

Glioblastoma (GBM), the most common primary malignant brain tumor, is a highly lethal form of cancer with a very limited set of treatment options. High heterogeneity in the tumor cell population and the invasive nature of these cells decrease the likely efficacy of traditional cancer treatments, thus requiring research into novel treatment options. The use of oncolytic viruses as potential therapeutics has been researched for some time. Zika virus (ZIKV) has demonstrated oncotropism and oncolytic effects on GBM stem cells (GSCs). To address the need for safe and effective GBM treatments, we designed an attenuated ZIKV strain (ZOL-1) that does not cause paralytic or neurological diseases in mouse models compared with unmodified ZIKV. Importantly, we found that patient-derived GBM tumors exhibited susceptibility (responders) and non-susceptibility (non-responders) to ZOL-1-mediated tumor cell killing, as evidenced by differential apoptotic cell death and cell viability upon ZOL-1 treatment. The oncolytic effect observed in responder cells was seen both in vitro in neurosphere models and in vivo upon xenograft. Finally, we observed that the use of ZOL-1 as combination therapy with multiple PI3K-AKT inhibitors in non-responder GBM resulted in enhanced chemotherapeutic efficacy. Altogether, this study establishes ZOL-1 as a safe and effective treatment against GBM and provides a foundation to conduct further studies evaluating its potential as an effective adjuvant with other chemotherapies and kinase inhibitors.

Funder

NIH

National Institutes of Health

Publisher

MDPI AG

Subject

General Medicine

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