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 journalArticlepeer-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

Vancouver

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 -