Actinomycin D Downregulates Sox2 and Improves Survival in Preclinical Models of Recurrent GlioblastomaCitation formats

  • External authors:
  • Jessica T Taylor
  • Alina Pandele
  • Erica Nathan
  • Gabriella Forte
  • Helen Parker
  • Egor Zindy
  • Konstantina Karabatsou
  • Martin McCabe
  • Catherine McBain
  • Brian W Bigger

Standard

Actinomycin D Downregulates Sox2 and Improves Survival in Preclinical Models of Recurrent Glioblastoma. / Taylor, Jessica T; Ellison, Stuart; Pandele, Alina; Wood, Shaun; Nathan, Erica; Forte, Gabriella; Parker, Helen; Zindy, Egor; Elvin, Mark; Dickson, Alan; Williams, Kaye J; Karabatsou, Konstantina; McCabe, Martin; McBain, Catherine; Bigger, Brian W.

In: Neuro-Oncology, Vol. 22, No. 9, 30.03.2020, p. 1289-1301.

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

Harvard

Taylor, JT, Ellison, S, Pandele, A, Wood, S, Nathan, E, Forte, G, Parker, H, Zindy, E, Elvin, M, Dickson, A, Williams, KJ, Karabatsou, K, McCabe, M, McBain, C & Bigger, BW 2020, 'Actinomycin D Downregulates Sox2 and Improves Survival in Preclinical Models of Recurrent Glioblastoma', Neuro-Oncology, vol. 22, no. 9, pp. 1289-1301. https://doi.org/10.1093/neuonc/noaa051

APA

Taylor, J. T., Ellison, S., Pandele, A., Wood, S., Nathan, E., Forte, G., Parker, H., Zindy, E., Elvin, M., Dickson, A., Williams, K. J., Karabatsou, K., McCabe, M., McBain, C., & Bigger, B. W. (2020). Actinomycin D Downregulates Sox2 and Improves Survival in Preclinical Models of Recurrent Glioblastoma. Neuro-Oncology, 22(9), 1289-1301. https://doi.org/10.1093/neuonc/noaa051

Vancouver

Taylor JT, Ellison S, Pandele A, Wood S, Nathan E, Forte G et al. Actinomycin D Downregulates Sox2 and Improves Survival in Preclinical Models of Recurrent Glioblastoma. Neuro-Oncology. 2020 Mar 30;22(9):1289-1301. https://doi.org/10.1093/neuonc/noaa051

Author

Taylor, Jessica T ; Ellison, Stuart ; Pandele, Alina ; Wood, Shaun ; Nathan, Erica ; Forte, Gabriella ; Parker, Helen ; Zindy, Egor ; Elvin, Mark ; Dickson, Alan ; Williams, Kaye J ; Karabatsou, Konstantina ; McCabe, Martin ; McBain, Catherine ; Bigger, Brian W. / Actinomycin D Downregulates Sox2 and Improves Survival in Preclinical Models of Recurrent Glioblastoma. In: Neuro-Oncology. 2020 ; Vol. 22, No. 9. pp. 1289-1301.

Bibtex

@article{9a3fffecea0b448abc10a469ced32265,
title = "Actinomycin D Downregulates Sox2 and Improves Survival in Preclinical Models of Recurrent Glioblastoma",
abstract = "BACKGROUND: Glioblastoma (GBM) has been extensively researched over the last few decades, yet despite aggressive multi-modal treatment, recurrence is inevitable and second-line treatment options are limited. Here, we demonstrate how high throughput screening (HTS) in multicellular spheroids can generate physiologically relevant patient chemosensitivity data using patient-derived cells in a rapid and cost-effective manner. Our HTS system identified ACTD to be highly cytotoxic over a panel of twelve patient-derived glioma stem-like cell lines (GSCs). Actinomycin D (ACTD) is antineoplastic antibiotic used in the treatment of childhood cancers. Here, we validate ACTD as a potential repurposed therapeutic for glioblastoma in three-dimensional GSC cultures and patient-derived xenograft models of recurrent glioblastoma.METHODS: Twelve patient-derived GSCs were screened at 10µM, as multicellular spheroids, in a 384-well serum-free assay with 133 FDA-approved compounds. GSCs were then treated in vitro with ACTD at established IC50 concentrations. Downregulation of Sox2, a stem-cell transcription factor, was investigated via western blot and through immunohistological assessment of murine brain tissue.RESULTS: Treatment with ACTD was shown to significantly reduce tumor growth in two recurrent GBM (rGBM) patient-derived models and significantly increased survival. ACTD is also shown to specifically downregulate the expression of Sox2 both in vitro and in vivo.CONCLUSION: These findings indicate that, as predicted by our HTS, ACTD could deplete the cancer stem cell population within the tumor mass, ultimately leading to a delay in tumor progression.",
author = "Taylor, {Jessica T} and Stuart Ellison and Alina Pandele and Shaun Wood and Erica Nathan and Gabriella Forte and Helen Parker and Egor Zindy and Mark Elvin and Alan Dickson and Williams, {Kaye J} and Konstantina Karabatsou and Martin McCabe and Catherine McBain and Bigger, {Brian W}",
note = "Publisher Copyright: {\textcopyright} The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.",
year = "2020",
month = mar,
day = "30",
doi = "10.1093/neuonc/noaa051",
language = "English",
volume = "22",
pages = "1289--1301",
journal = "Neuro-Oncology",
issn = "1522-8517",
publisher = "Oxford University Press",
number = "9",

}

RIS

TY - JOUR

T1 - Actinomycin D Downregulates Sox2 and Improves Survival in Preclinical Models of Recurrent Glioblastoma

AU - Taylor, Jessica T

AU - Ellison, Stuart

AU - Pandele, Alina

AU - Wood, Shaun

AU - Nathan, Erica

AU - Forte, Gabriella

AU - Parker, Helen

AU - Zindy, Egor

AU - Elvin, Mark

AU - Dickson, Alan

AU - Williams, Kaye J

AU - Karabatsou, Konstantina

AU - McCabe, Martin

AU - McBain, Catherine

AU - Bigger, Brian W

N1 - Publisher Copyright: © The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

PY - 2020/3/30

Y1 - 2020/3/30

N2 - BACKGROUND: Glioblastoma (GBM) has been extensively researched over the last few decades, yet despite aggressive multi-modal treatment, recurrence is inevitable and second-line treatment options are limited. Here, we demonstrate how high throughput screening (HTS) in multicellular spheroids can generate physiologically relevant patient chemosensitivity data using patient-derived cells in a rapid and cost-effective manner. Our HTS system identified ACTD to be highly cytotoxic over a panel of twelve patient-derived glioma stem-like cell lines (GSCs). Actinomycin D (ACTD) is antineoplastic antibiotic used in the treatment of childhood cancers. Here, we validate ACTD as a potential repurposed therapeutic for glioblastoma in three-dimensional GSC cultures and patient-derived xenograft models of recurrent glioblastoma.METHODS: Twelve patient-derived GSCs were screened at 10µM, as multicellular spheroids, in a 384-well serum-free assay with 133 FDA-approved compounds. GSCs were then treated in vitro with ACTD at established IC50 concentrations. Downregulation of Sox2, a stem-cell transcription factor, was investigated via western blot and through immunohistological assessment of murine brain tissue.RESULTS: Treatment with ACTD was shown to significantly reduce tumor growth in two recurrent GBM (rGBM) patient-derived models and significantly increased survival. ACTD is also shown to specifically downregulate the expression of Sox2 both in vitro and in vivo.CONCLUSION: These findings indicate that, as predicted by our HTS, ACTD could deplete the cancer stem cell population within the tumor mass, ultimately leading to a delay in tumor progression.

AB - BACKGROUND: Glioblastoma (GBM) has been extensively researched over the last few decades, yet despite aggressive multi-modal treatment, recurrence is inevitable and second-line treatment options are limited. Here, we demonstrate how high throughput screening (HTS) in multicellular spheroids can generate physiologically relevant patient chemosensitivity data using patient-derived cells in a rapid and cost-effective manner. Our HTS system identified ACTD to be highly cytotoxic over a panel of twelve patient-derived glioma stem-like cell lines (GSCs). Actinomycin D (ACTD) is antineoplastic antibiotic used in the treatment of childhood cancers. Here, we validate ACTD as a potential repurposed therapeutic for glioblastoma in three-dimensional GSC cultures and patient-derived xenograft models of recurrent glioblastoma.METHODS: Twelve patient-derived GSCs were screened at 10µM, as multicellular spheroids, in a 384-well serum-free assay with 133 FDA-approved compounds. GSCs were then treated in vitro with ACTD at established IC50 concentrations. Downregulation of Sox2, a stem-cell transcription factor, was investigated via western blot and through immunohistological assessment of murine brain tissue.RESULTS: Treatment with ACTD was shown to significantly reduce tumor growth in two recurrent GBM (rGBM) patient-derived models and significantly increased survival. ACTD is also shown to specifically downregulate the expression of Sox2 both in vitro and in vivo.CONCLUSION: These findings indicate that, as predicted by our HTS, ACTD could deplete the cancer stem cell population within the tumor mass, ultimately leading to a delay in tumor progression.

UR - http://www.scopus.com/inward/record.url?scp=85092332161&partnerID=8YFLogxK

U2 - 10.1093/neuonc/noaa051

DO - 10.1093/neuonc/noaa051

M3 - Article

C2 - 32227096

VL - 22

SP - 1289

EP - 1301

JO - Neuro-Oncology

JF - Neuro-Oncology

SN - 1522-8517

IS - 9

ER -