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Updated: Jun 25, 2025
Combination Radiotherapy in an Orthotopic Mouse Brain Tumor Model
Published on: March 6, 2012
BET bromodomain inhibition potentiates radiosensitivity in models of H3K27-altered diffuse midline glioma
Jun Watanabe1,2,3,4, Matthew R Clutter5, Michael J Gullette6
1Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Abstract:
Diffuse midline glioma (DMG) H3K27-altered is one of the most malignant childhood cancers. Radiation therapy remains the only effective treatment yet provides a 5-year survival rate of only 1%. Several clinical trials have attempted to enhance radiation antitumor activity using radiosensitizing agents, although none have been successful. Given this, there is a critical need for identifying effective therapeutics to enhance radiation sensitivity for the treatment of DMG. Using high-throughput radiosensitivity screening, we identified bromo- and extraterminal domain (BET) protein inhibitors as potent radiosensitizers in DMG cells. Genetic and pharmacologic inhibition of BET bromodomain activity reduced DMG cell proliferation and enhanced radiation-induced DNA damage by inhibiting DNA repair pathways. RNA-Seq and the CUT&RUN (cleavage under targets and release using nuclease) analysis showed that BET bromodomain inhibitors regulated the expression of DNA repair genes mediated by H3K27 acetylation at enhancers. BET bromodomain inhibitors enhanced DMG radiation response in patient-derived xenografts as well as genetically engineered mouse models. Together, our results highlight BET bromodomain inhibitors as potential radiosensitizer and provide a rationale for developing combination therapy with radiation for the treatment of DMG.
Insights
New research identifies bromo- and extraterminal domain (BET) protein inhibitors as potent radiosensitizers for diffuse midline glioma (DMG). These inhibitors enhance radiation therapy effectiveness by reducing cancer cell proliferation and DNA repair in preclinical models.
Area of Science:
- Oncology
- Cancer Biology
- Radiation Oncology
Background:
- Diffuse midline glioma (DMG) H3K27-altered is a highly aggressive pediatric cancer with poor prognosis.
- Current treatments, primarily radiation therapy, offer limited survival benefits, necessitating novel therapeutic strategies.
Purpose of the Study:
- To identify novel radiosensitizing agents capable of enhancing the efficacy of radiation therapy for DMG.
- To investigate the therapeutic potential of bromo- and extraterminal domain (BET) protein inhibitors in combination with radiation for DMG treatment.
Main Methods:
- High-throughput radiosensitivity screening to identify potential radiosensitizers.
- Genetic and pharmacologic inhibition of BET bromodomain activity.
- RNA-sequencing (RNA-Seq) and CUT&RUN (cleavage under targets and release using nuclease) assays.
- Evaluation in patient-derived xenografts and genetically engineered mouse models.
Main Results:
- BET protein inhibitors were identified as potent radiosensitizers in DMG cells.
- Inhibition of BET bromodomain activity reduced DMG cell proliferation and enhanced radiation-induced DNA damage by suppressing DNA repair pathways.
- BET inhibitors modulated the expression of DNA repair genes via H3K27 acetylation at enhancers.
- Combination therapy demonstrated enhanced DMG radiation response in preclinical models.
Conclusions:
- BET bromodomain inhibitors show significant promise as radiosensitizers for diffuse midline glioma.
- These findings provide a strong rationale for developing combination therapies involving BET inhibitors and radiation for DMG treatment.
