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Updated: Feb 26, 2026
Isolation, Enrichment, and Maintenance of Medulloblastoma Stem Cells
Published on: September 1, 2010
Dual PI3K/AKT and CDK4/6 inhibition reveals selective sensitivity in an SHH medulloblastoma stem cell model
Monika Lukoseviciute1, Madeleine Birgersson1, Paolo Ceriani1
1Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
Abstract:
Medulloblastoma (MB) is a brain tumor for which current treatments cause serious side effects and are not curative for all patients, highlighting the need for more effective and brain-protecting therapies. Recently, we combined phosphoinositide 3-kinase (PI3K) inhibitor (BYL719), fibroblast growth factor receptor (FGFR) inhibitor (JNJ-42756493) and cyclin-dependent kinase (CDK)4/6 inhibitor (PD-0332991) in MB cell lines, and discovered synergistic effects. In the current study, we investigate the most efficient therapies in a normal/tumorigenic neural stem cell model. A sonic hedgehog (SHH)-MB model, including a Gorlin syndrome patient neuroepithelial stem cell line (NES) and its tumor derivative (tNES), was used to evaluate single and combined treatments of PI3K, AKT, FGFR, and CDK4/6 inhibitors (BYL719, AZD5363, JNJ-42756493, and PD-0332991, respectively). Effects on viability, cell confluence and apoptosis were tested on NES and tNES cells cultured as 2D monolayers and 3D spheroids. We found that 2D tNES cells were generally more sensitive to the inhibitory effects of both single and combination treatments compared to 2D NES cells. In the 3D setting, all single drugs were more effective against tNES than NES, except for JNJ-42756493, which showed the opposite trend. Drug combinations in 3D cultures generally resulted in synergistic or additive effects on cell viability in NES and tNES. This study illustrates that single and combined administrations of PI3K, FGFR, CDK4/6, and AKT inhibitors in a NES/tNES model have dose-dependent and additive/synergistic anti-MB activity impacting tumor growth. Their effects on tNES cells were generally more pronounced than on NES; however, the difference in proliferative capacity between the cells should be considered.
Insights
New therapies combining PI3K, FGFR, CDK4/6, and AKT inhibitors show promise against medulloblastoma (MB). These drug combinations demonstrate synergistic effects, impacting tumor growth in neural stem cell models.
Area of Science:
- Oncology
- Molecular Biology
- Neuroscience
Background:
- Medulloblastoma (MB) treatments have significant side effects and are not universally curative.
- There is a critical need for more effective and brain-sparing therapeutic strategies for MB.
- Previous research indicated synergistic effects of combining PI3K, FGFR, and CDK4/6 inhibitors in MB cell lines.
Purpose of the Study:
- To investigate the efficacy of single and combined PI3K, AKT, FGFR, and CDK4/6 inhibitors in a normal/tumorigenic neural stem cell model.
- To evaluate treatment effects on viability, cell confluence, and apoptosis in both normal (NES) and tumor-derived (tNES) cells.
- To compare treatment outcomes in 2D monolayer and 3D spheroid culture systems.
Main Methods:
- Utilized a sonic hedgehog (SHH)-MB model with patient-derived neuroepithelial stem (NES) and tumor derivative (tNES) cell lines.
- Administered single and combination therapies using PI3K, AKT, FGFR, and CDK4/6 inhibitors (BYL719, AZD5363, JNJ-42756493, PD-0332991).
- Assessed cellular responses in 2D monolayers and 3D spheroids, measuring viability, confluence, and apoptosis.
Main Results:
- 2D tNES cells were generally more sensitive to inhibitory treatments than 2D NES cells.
- In 3D cultures, most single drugs were more effective against tNES than NES, with JNJ-42756493 showing the reverse trend.
- Drug combinations in 3D cultures exhibited synergistic or additive effects on cell viability in both NES and tNES cells.
- Treatment effects on tNES cells were generally more pronounced than on NES cells, considering proliferative differences.
Conclusions:
- Single and combined PI3K, FGFR, CDK4/6, and AKT inhibitors demonstrate dose-dependent anti-MB activity.
- These drug combinations show additive/synergistic effects, impacting medulloblastoma tumor growth.
- The study highlights the potential of these inhibitors as targeted therapies for medulloblastoma, with greater impact on tumor cells.
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