Glioblastoma is the most common primary brain cancer with around 12,000 cases diagnosed in the United States each year. Treatment options include surgery to remove the glioblastoma, radiation therapy, chemotherapy, tumor treating fields (TTF) therapy, or targeted drug therapy. However, only 10% of people survive five years of this grade IV cancer. Now researchers at the 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 improve the overall survival in mice with glioblastoma.
Their findings are published in the Journal of the National Cancer Institute in a paper titled, “Dopamine Receptor Antagonists, Radiation, and Cholesterol Biosynthesis in Mouse Models of Glioblastoma.”
“Glioblastoma is the deadliest brain tumor in adults and the standard-of-care consists of surgery followed by radiation and treatment with temozolomide,” wrote the researchers. “Overall survival times for patients suffering from glioblastoma are unacceptably low indicating an unmet need for novel treatment options.”
UCLA researchers previously reported that the first-generation dopamine receptor antagonist trifluoperazine in combination with radiation prolonged survival in mouse models of glioblastoma, but ultimately, the mice become resistant to the therapy. The researchers used quetiapine, a second-generation dopamine receptor antagonist, to overcome resistance. Quetiapine enhanced the efficacy of radiotherapy in glioblastoma and generated a metabolic vulnerability in the lipid homeostasis. The observation that the combination induced the cholesterol biosynthesis pathway allowed the researchers to target this process with statins.
“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.”
The team tested the approach using patient-derived glioblastoma lines provided by the Biospecimen and Pathology Core of the UCLA SPORE in Brain Cancer. Quetiapine was identified in a screen of dopamine receptor antagonists for their ability to prevent phenotype conversion of non-tumorigenic glioblastoma cells into radiation-induced glioma initiating cells. The researchers chose atorvastatin because it is able to cross the blood-brain barrier.
The dopamine receptor antagonist quetiapine helped reduce glioma cell self-renewal in vitro and combined treatment of mice with quetiapine and radiation prolonged the survival of glioma-bearing mice.
“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,” concluded the researchers.
Their study may potentially lead to improving survival rates in this devastating disease.
