Abstract
Abstract The tumor targeted oncolytic adenovirus Delta24-RGD is currently under phase I/II investigation for the malignant brain tumor glioblastoma. Despite encouraging results, the efficacy of oncolytic virotherapy still requires improvements due to heterogeneous or poor responses. In this study, we performed a screen of 446 clinically applied drugs to identify those that enhance Delta24-RGD oncolysis in glioblastoma. Cell viability was determined five days post-infection in Delta24-RGD resistant patient-derived glioblastoma stem cell (GSCs) cultures. Potential ‘hits’ were tested for synergistic viral sensitization using the Chou-Talalay method. Effects on viral infection and replication were investigated using Ad-Luc-RGD and Delta24-RGD-GFP viruses, and apoptosis and necrosis were evaluated using caspase-3/7 and lactate dehydrogenase (LDH) assays. Selection based on the efficacy of combination treatment led to the identification of ten drugs as potential Delta24-RGD sensitizers from the initial screen. Further analysis of effects on viral replication, synergistic interactions and ability to penetrate the blood-brain barrier narrowed this down to four remaining compounds, fluphenazine, indirubin, lofepramine and ranolazine. These four agents increased caspase-3/7 activity and fluphenazine also increased LDH levels in combination with Delta24-RGD. Fluphenazine, indirubin, lofepramine and ranolazine sensitized 12/12, 11/12, 9/12 and 11/12 distinct GSC cultures to Delta24-RGD, respectively. In conclusion, a clinical compound screen on glioblastoma stem cells in combination with in vitro mechanistic studies, revealed four highly effective compounds that sensitize GSCs to Delta24-RGD oncolytic therapy. Citation Format: Lotte ME Berghauser Pont, Rutger Balvers, Jenneke Kloezeman, Michal O. Nowicki, Andreas Kremer, E. Antonio Chiocca, Sieger Leenstra, Clemens MF Dirven, Sean Lawler, Martine LM Lamfers. In vitro compound screening identifies enhancers of adenoviral oncolysis with Delta24-RGD in patient-derived glioblastoma stem cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 299. doi:10.1158/1538-7445.AM2015-299
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
