In vitro screening of clinical drugs identifies sensitizers of oncolytic viral therapy in glioblastoma stem-like cells

Lotte Berghauser Pont; Rutger Balvers; Jenneke Kloezeman; MO Nowicki; W van den Bossche; Andreas Kremer; H Wakimoto; BG van den Hoogen; Sieger Leenstra; Clemens Dirven; EA Chiocca; SE Lawler; Martine Lamfers

doi:10.1038/gt.2015.72

In vitro screening of clinical drugs identifies sensitizers of oncolytic viral therapy in glioblastoma stem-like cells

Lotte Berghauser Pont, Rutger Balvers, Jenneke Kloezeman, MO Nowicki, W van den Bossche, Andreas Kremer, H Wakimoto, BG van den Hoogen, Sieger Leenstra, Clemens Dirven, EA Chiocca, SE Lawler, Martine Lamfers

Research output: Contribution to journal › Article › Academic › peer-review

14 Citations (Scopus)

Abstract

Oncolytic viruses (OV) have broad potential as an adjuvant for the treatment of solid tumors. The present study addresses the feasibility of clinically applicable drugs to enhance the oncolytic potential of the OV Delta24-RGD in glioblastoma. In total, 446 drugs were screened for their viral sensitizing properties in glioblastoma stem-like cells (GSCs) in vitro. Validation was done for 10 drugs to determine synergy based on the Chou Talalay assay. Mechanistic studies were undertaken to assess viability, replication efficacy, viral infection enhancement and cell death pathway induction in a selected panel of drugs. Four viral sensitizers (fluphenazine, indirubin, lofepramine and ranolazine) were demonstrated to reproducibly synergize with Delta24-RGD in multiple assays. After validation, we underscored general applicability by testing candidate drugs in a broader context of a panel of different GSCs, various solid tumor models and multiple OVs. Overall, this study identified four viral sensitizers, which synergize with Delta24-RGD and two other strains of OVs. The viral sensitizers interact with infection, replication and cell death pathways to enhance efficacy of the OV.

Original language	Undefined/Unknown
Pages (from-to)	947-959
Number of pages	13
Journal	Gene Therapy
Volume	22
Issue number	12
DOIs	https://doi.org/10.1038/gt.2015.72
Publication status	Published - 2015

Research programs

EMC MM-03-44-06
EMC MM-04-27-01
EMC OR-01-45-01

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10.1038/gt.2015.72

Cite this

Berghauser Pont, L., Balvers, R., Kloezeman, J., Nowicki, MO., van den Bossche, W., Kremer, A., Wakimoto, H., van den Hoogen, BG., Leenstra, S., Dirven, C., Chiocca, EA., Lawler, SE., & Lamfers, M. (2015). In vitro screening of clinical drugs identifies sensitizers of oncolytic viral therapy in glioblastoma stem-like cells. Gene Therapy, 22(12), 947-959. https://doi.org/10.1038/gt.2015.72

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title = "In vitro screening of clinical drugs identifies sensitizers of oncolytic viral therapy in glioblastoma stem-like cells",

abstract = "Oncolytic viruses (OV) have broad potential as an adjuvant for the treatment of solid tumors. The present study addresses the feasibility of clinically applicable drugs to enhance the oncolytic potential of the OV Delta24-RGD in glioblastoma. In total, 446 drugs were screened for their viral sensitizing properties in glioblastoma stem-like cells (GSCs) in vitro. Validation was done for 10 drugs to determine synergy based on the Chou Talalay assay. Mechanistic studies were undertaken to assess viability, replication efficacy, viral infection enhancement and cell death pathway induction in a selected panel of drugs. Four viral sensitizers (fluphenazine, indirubin, lofepramine and ranolazine) were demonstrated to reproducibly synergize with Delta24-RGD in multiple assays. After validation, we underscored general applicability by testing candidate drugs in a broader context of a panel of different GSCs, various solid tumor models and multiple OVs. Overall, this study identified four viral sensitizers, which synergize with Delta24-RGD and two other strains of OVs. The viral sensitizers interact with infection, replication and cell death pathways to enhance efficacy of the OV.",

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Berghauser Pont, L, Balvers, R, Kloezeman, J, Nowicki, MO, van den Bossche, W, Kremer, A, Wakimoto, H, van den Hoogen, BG , Leenstra, S , Dirven, C, Chiocca, EA, Lawler, SE & Lamfers, M 2015, 'In vitro screening of clinical drugs identifies sensitizers of oncolytic viral therapy in glioblastoma stem-like cells', Gene Therapy, vol. 22, no. 12, pp. 947-959. https://doi.org/10.1038/gt.2015.72

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T1 - In vitro screening of clinical drugs identifies sensitizers of oncolytic viral therapy in glioblastoma stem-like cells

AU - Berghauser Pont, Lotte

AU - Balvers, Rutger

AU - Kloezeman, Jenneke

AU - Nowicki, MO

AU - van den Bossche, W

AU - Kremer, Andreas

AU - Wakimoto, H

AU - van den Hoogen, BG

AU - Leenstra, Sieger

AU - Dirven, Clemens

AU - Chiocca, EA

AU - Lawler, SE

AU - Lamfers, Martine

PY - 2015

Y1 - 2015

N2 - Oncolytic viruses (OV) have broad potential as an adjuvant for the treatment of solid tumors. The present study addresses the feasibility of clinically applicable drugs to enhance the oncolytic potential of the OV Delta24-RGD in glioblastoma. In total, 446 drugs were screened for their viral sensitizing properties in glioblastoma stem-like cells (GSCs) in vitro. Validation was done for 10 drugs to determine synergy based on the Chou Talalay assay. Mechanistic studies were undertaken to assess viability, replication efficacy, viral infection enhancement and cell death pathway induction in a selected panel of drugs. Four viral sensitizers (fluphenazine, indirubin, lofepramine and ranolazine) were demonstrated to reproducibly synergize with Delta24-RGD in multiple assays. After validation, we underscored general applicability by testing candidate drugs in a broader context of a panel of different GSCs, various solid tumor models and multiple OVs. Overall, this study identified four viral sensitizers, which synergize with Delta24-RGD and two other strains of OVs. The viral sensitizers interact with infection, replication and cell death pathways to enhance efficacy of the OV.

AB - Oncolytic viruses (OV) have broad potential as an adjuvant for the treatment of solid tumors. The present study addresses the feasibility of clinically applicable drugs to enhance the oncolytic potential of the OV Delta24-RGD in glioblastoma. In total, 446 drugs were screened for their viral sensitizing properties in glioblastoma stem-like cells (GSCs) in vitro. Validation was done for 10 drugs to determine synergy based on the Chou Talalay assay. Mechanistic studies were undertaken to assess viability, replication efficacy, viral infection enhancement and cell death pathway induction in a selected panel of drugs. Four viral sensitizers (fluphenazine, indirubin, lofepramine and ranolazine) were demonstrated to reproducibly synergize with Delta24-RGD in multiple assays. After validation, we underscored general applicability by testing candidate drugs in a broader context of a panel of different GSCs, various solid tumor models and multiple OVs. Overall, this study identified four viral sensitizers, which synergize with Delta24-RGD and two other strains of OVs. The viral sensitizers interact with infection, replication and cell death pathways to enhance efficacy of the OV.

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DO - 10.1038/gt.2015.72

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