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Updated: Dec 28, 2025
A Protocol for Rapid Post-mortem Cell Culture of Diffuse Intrinsic Pontine Glioma DIPG
Published on: March 7, 2017
Rationale for the advancement of PI3K pathway inhibitors for personalized chordoma therapy
N L Michmerhuizen1,2, J H Owen1, M E Heft Neal1
1Department of Otolaryngology - Head and Neck Surgery, University of Michigan Medical School, 1150 E. Medical Center Dr., 9301B MSRB3, Ann Arbor, MI, 48109-0602, USA.
Purpose:
Chordomas are rare and serious tumors with few effective treatments outside of aggressive surgery and radiation. Targeted therapies may present a more effective option for a subset of patients with lesions possessing certain genetic biomarkers.
Methods:
A small molecule inhibitor library was tested in patient-derived UM-Chor1 cells to identify targeted therapies with potential efficacy. Targeted exome sequencing of UM-Chor1 and UM-Chor2 cells was performed to investigate genetic aberrations in relevant pathways. Chordoma cell lines were treated with inhibitors of the phosphotidylinositol 3-kinase (PI3K), epidermal growth factor receptor (EGFR), and cyclin dependent kinase (CDK) pathways, and responses were determined using resazurin cell viability assays, Annexin V apoptosis assays, and western blotting. Pan-PI3K inhibitor BKM120 was also tested in five chordoma xenograft models.
Results:
Unbiased small molecule profiling nominated PI3K-AKT-mTOR pathway inhibitors as a promising therapy in chordoma, and genetic analyses of UM-Chor1 and UM-Chor2 cell lines revealed aberrations in PTEN, EGFR, and CDKN2A. Treatment of UM-Chor1 and UM-Chor2 with targeted PI3K, EGFR, and CDK inhibitors inhibited growth and proliferation and induced apoptosis more robustly than imatinib, a currently used chordoma therapy. Furthermore, BKM120 significantly inhibited tumor growth in a subset of the xenograft models tested.
Conclusion:
Targeted therapies, especially those inhibiting PI3K, display promising effects in multiple chordoma cell line and xenograft models. Nevertheless, the limited effects of PI3K, EGFR, and CDK targeting agents in other models reveal the presence of resistance mechanisms, which motivates future research to both identify biomarkers of response and develop combination therapies.
Insights
Targeted therapies, particularly PI3K inhibitors, show promise against chordoma tumors by inhibiting growth and inducing apoptosis. Further research is needed to overcome resistance mechanisms and identify biomarkers for effective treatment strategies.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Chordomas are rare, aggressive bone tumors with limited treatment options beyond surgery and radiation.
- Targeted therapies offer potential for patients with specific genetic biomarkers in their tumors.
Purpose of the Study:
- To identify effective targeted therapies for chordoma by screening small molecule inhibitors.
- To investigate genetic aberrations in chordoma cell lines and assess the efficacy of pathway-specific inhibitors.
Main Methods:
- Screening of a small molecule inhibitor library against patient-derived chordoma cells (UM-Chor1).
- Targeted exome sequencing of chordoma cell lines (UM-Chor1, UM-Chor2) to identify genetic alterations.
- Treatment of cell lines with inhibitors targeting PI3K, EGFR, and CDK pathways, followed by viability and apoptosis assays.
- Evaluation of a PI3K inhibitor (BKM120) in chordoma xenograft models.
Main Results:
- PI3K-AKT-mTOR pathway inhibitors emerged as promising therapeutic candidates.
- Genetic analysis revealed aberrations in PTEN, EGFR, and CDKN2A in chordoma cell lines.
- Targeted inhibitors of PI3K, EGFR, and CDK demonstrated superior efficacy in inhibiting growth and inducing apoptosis compared to imatinib.
- The PI3K inhibitor BKM120 significantly reduced tumor growth in a subset of xenograft models.
Conclusions:
- Targeted therapies, especially PI3K inhibitors, show significant potential in preclinical chordoma models.
- The presence of resistance mechanisms necessitates further investigation into biomarkers and combination therapies for chordoma treatment.
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