A new combination treatment approach improves overall survival in mice with glioblastoma

Results

In a study of mice, researchers at UCLA Jonsson Comprehensive Cancer Center have identified a new approach that combines an anti-psychotic drug, a statin used to lower high cholesterol levels, and radiation to survive complete in mice with developing glioblastoma. Glioblastoma is one of the most deadly and most difficult to treat brain tumors. The researchers found that the triple combination extended 4-fold median survival compared to radiation alone.

Background

Radiation therapy is part of the standard-of-care treatment regimen for glioblastoma, often helping with patient survival. However, survival rates have not improved significantly over the last two decades and efforts to improve the effectiveness of radiotherapy through the use of medications have been thwarted by the usual acute toxicity of the drugs and the inability to enter the blood-brain barrier.

UCLA researchers previously reported that the first-generation dopamine receptor antagonist trifluoperazine in combination with long-lasting radiation in mouse models of glioblastoma, but ultimately, the mice resist the cure. To help overcome this resistance, the team used quetiapine, a second-generation dopamine receptor antagonist, which not only demonstrated the effectiveness of radiotherapy in glioblastoma but also created metabolic vulnerabilities in lipid homeostasis. Discovering that the fusion stimulated the cholesterol biosynthesis pathway allowed the team to target this process with statins.

Method

The team tested the procedure using glioblastoma lines derived from patients given the Biospecimen and Core Pathology of the UCLA SPORE in Brain Cancer. Quetiapine was identified in a screen of dopamine receptor antagonists for its ability to inhibit the phenotype conversion of non-tumorigenic glioblastoma cells into radiation-induced glioma onset. Atorvastatin (Lipitor) was chosen because of its known ability to cross the blood-brain barrier.

Impact

Although radiation alone prolongs the survival of glioblastoma, attempts to improve the treatment have been unsuccessful. The results of the study provide evidence that the use of a dopamine receptor antagonist in combination with Atorvastatin and radiation may help extend survival for people with glioblastoma. The combination therapy also includes FDA-approved drugs that can be quickly translated into clinical trials.