4.1 Article

A Cytotoxic Three-Dimensional-Spheroid, High-Throughput Assay Using Patient-Derived Glioma Stem Cells

Journal

SLAS DISCOVERY
Volume 23, Issue 8, Pages 842-849

Publisher

SAGE PUBLICATIONS INC
DOI: 10.1177/2472555218775055

Keywords

glioblastoma; 3D culture; cytotoxicity; approved drug library

Funding

  1. National Cancer Institute of the National Institutes of Health [R33CA206949]
  2. FCBTR/ABC2 Brain Tumor Grants Program

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Glioblastoma (GBM) is the most aggressive primary brain cancer with an average survival time after diagnosis of only 12-14 months, with few (<5%) long-term survivors. A growing body of work suggests that GBMs contain a small population of glioma stem cells (GSCs) that are thought to be major contributors to treatment resistance and disease relapse. Identifying compounds that modulate GSC proliferation would provide highly valuable molecular probes of GSC-directed signaling. However, targeting GSCs pharmacologically has been challenging. Patient-derived GSCs can be cultured as neurospheres, and in vivo these cells functionally recapitulate the heterogeneity of the original tumor. Using patient-derived GSC-enriched cultures, we have developed a 1536-well spheroid-based proliferation assay and completed a pilot screen, testing similar to 3300 compounds comprising approved drugs. This cytotoxic and automation-friendly assay yielded a signal-to-background (S/B) ratio of 161.3 +/- 7.5 and Z' of 0.77 +/- 0.02, demonstrating its robustness. Importantly, compounds were identified with anti-GSC activity, demonstrating the applicability of this assay for large-scale high-throughput screening (HTS).

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