Related Experiment Video
Updated: Nov 18, 2025
Combination Radiotherapy in an Orthotopic Mouse Brain Tumor Model
Published on: March 6, 2012
Dopamine Receptor Antagonists, Radiation, and Cholesterol Biosynthesis in Mouse Models of Glioblastoma
Kruttika Bhat1, Mohammad Saki1, Fei Cheng1
1Department of Radiation Oncology, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, CA , USA.
Background:
Glioblastoma is the deadliest brain tumor in adults, and the standard of care consists of surgery followed by radiation and treatment with temozolomide. Overall survival times for patients suffering from glioblastoma are unacceptably low indicating an unmet need for novel treatment options.
Methods:
Using patient-derived HK-157, HK-308, HK-374, and HK-382 glioblastoma lines, the GL261 orthotopic mouse models of glioblastoma, and HK-374 patient-derived orthotopic xenografts, we tested the effect of radiation and the dopamine receptor antagonist quetiapine on glioblastoma self-renewal in vitro and survival in vivo. A possible resistance mechanism was investigated using RNA-sequencing. The blood-brain-barrier-penetrating statin atorvastatin was used to overcome this resistance mechanism. All statistical tests were 2-sided.
Results:
Treatment of glioma cells with the dopamine receptor antagonist quetiapine reduced glioma cell self-renewal in vitro, and combined treatment of mice with quetiapine and radiation prolonged the survival of glioma-bearing mice. The combined treatment induced the expression of genes involved in cholesterol biosynthesis. This rendered GL261 and HK-374 orthotopic tumors vulnerable to simultaneous treatment with atorvastatin and further statistically significantly prolonged the survival of C57BL/6 (n = 10 to 16 mice per group; median survival not reached; log-rank test, P < .001) and NOD Scid gamma mice (n = 8 to 21 mice per group; hazard ratio = 3.96, 95% confidence interval = 0.29 to 12.40; log-rank test, P < .001), respectively.
Conclusions:
Our results indicate promising therapeutic efficacy with the triple combination of quetiapine, atorvastatin, and radiation treatment against glioblastoma without increasing the toxicity of radiation. With both drugs readily available for clinical use, our study could be rapidly translated into a clinical trial.
Insights
A novel triple therapy combining quetiapine, atorvastatin, and radiation shows promise for treating glioblastoma (deadly brain tumors). This combination therapy may improve patient survival without increasing radiation toxicity, paving the way for clinical trials.
Area of Science:
- Neuro-oncology
- Pharmacology
- Cancer Research
Background:
- Glioblastoma is the most lethal adult brain tumor with poor survival rates.
- Current standard treatments (surgery, radiation, temozolomide) have limitations.
- There is a critical need for novel glioblastoma treatment strategies.
Purpose of the Study:
- To investigate the efficacy of quetiapine and radiation in treating glioblastoma.
- To explore a potential resistance mechanism and a method to overcome it.
- To evaluate a novel triple combination therapy for glioblastoma.
Main Methods:
- Utilized patient-derived glioblastoma cell lines and orthotopic mouse models.
- Assessed the effects of quetiapine and radiation on glioblastoma self-renewal and survival.
- Employed RNA-sequencing to identify resistance mechanisms and atorvastatin to overcome them.
Main Results:
- Quetiapine reduced glioblastoma cell self-renewal in vitro.
- Combined quetiapine and radiation prolonged survival in glioblastoma-bearing mice.
- The triple combination of quetiapine, atorvastatin, and radiation significantly extended survival in mouse models.
Conclusions:
- The triple therapy demonstrates promising therapeutic efficacy against glioblastoma.
- This combination strategy does not increase radiation toxicity.
- The readily available drugs support rapid translation to clinical trials for glioblastoma treatment.
