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

Research output: Contribution to journalArticlepeer-review

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

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.

Bibliographical metadata

Original languageEnglish
JournalNeuro-Oncology
Early online date30 Mar 2020
DOIs
Publication statusE-pub ahead of print - 30 Mar 2020

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