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Updated: Dec 7, 2025
Combination Radiotherapy in an Orthotopic Mouse Brain Tumor Model
Published on: March 6, 2012
Tumor genotype dictates radiosensitization after Atm deletion in primary brainstem glioma models
Katherine Deland1, Bryce F Starr1, Joshua S Mercer1
1Department of Radiation Oncology.
Abstract:
Diffuse intrinsic pontine glioma (DIPG) kills more children than any other type of brain tumor. Despite clinical trials testing many chemotherapeutic agents, palliative radiotherapy remains the standard treatment. Here, we utilized Cre/loxP technology to show that deleting Ataxia telangiectasia mutated (Atm) in primary mouse models of DIPG can enhance tumor radiosensitivity. Genetic deletion of Atm improved survival of mice with p53-deficient but not p53 wild-type gliomas after radiotherapy. Similar to patients with DIPG, mice with p53 wild-type tumors had improved survival after radiotherapy independent of Atm deletion. Primary p53 wild-type tumor cell lines induced proapoptotic genes after radiation and repressed the NRF2 target, NAD(P)H quinone dehydrogenase 1 (Nqo1). Tumors lacking p53 and Ink4a/Arf expressed the highest level of Nqo1 and were most resistant to radiation, but deletion of Atm enhanced the radiation response. These results suggest that tumor genotype may determine whether inhibition of ATM during radiotherapy will be an effective clinical approach to treat DIPGs.
Insights
Deleting Ataxia telangiectasia mutated (Atm) improved survival in pediatric brain tumor models with specific genetic profiles after radiation therapy. Tumor genotype is key to determining if ATM inhibition enhances radiotherapy for diffuse intrinsic pontine glioma (DIPG).
Area of Science:
- Pediatric neuro-oncology
- Cancer genetics
- Radiation oncology
Background:
- Diffuse intrinsic pontine glioma (DIPG) is a fatal pediatric brain tumor with limited treatment options.
- Palliative radiotherapy is the current standard, but novel therapeutic strategies are urgently needed.
Purpose of the Study:
- To investigate the role of Ataxia telangiectasia mutated (Atm) deletion in enhancing radiosensitivity in DIPG mouse models.
- To determine if tumor genotype influences the efficacy of ATM inhibition combined with radiotherapy.
Main Methods:
- Utilized Cre/loxP technology to generate primary mouse models of DIPG.
- Assessed the impact of Atm deletion on tumor radiosensitivity and mouse survival.
- Analyzed gene expression, including proapoptotic genes and NRF2 targets like NAD(P)H quinone dehydrogenase 1 (Nqo1).
Main Results:
- Genetic deletion of Atm enhanced tumor radiosensitivity and improved survival in p53-deficient DIPG models after radiotherapy.
- p53 wild-type DIPG models showed improved survival with radiotherapy independent of Atm deletion.
- Tumors lacking p53 and Ink4a/Arf exhibited high Nqo1 expression and radiation resistance, but Atm deletion improved their response to radiation.
Conclusions:
- Tumor genotype significantly influences the effectiveness of ATM inhibition during radiotherapy for DIPG.
- Targeting ATM may be a viable strategy for specific DIPG subtypes, particularly those with p53 deficiency.
- Further research is warranted to explore genotype-specific therapeutic approaches for DIPG.
