Metabolic

Mixture remedy with radiation reveals promise in treating glioblastoma

UCLA RESEARCH ALERT

RESULTS

In a study in mice, researchers at the UCLA Jonsson Comprehensive Cancer Center identified a new approach that combines an antipsychotic, a statin used to lower high cholesterol, and radiation to improve overall survival in mice with glioblastoma. Glioblastoma is one of the deadliest and most difficult to treat brain tumors. The researchers found that the triple combination increased median survival four times compared to radiation alone.

BACKGROUND

Radiation therapy is part of the standard treatment regimen for glioblastoma and often helps to extend patient survival. However, survival times have not improved significantly in the past two decades, and attempts to improve the effectiveness of radiation therapy through the use of drugs have been hampered by the drugs’ normal tissue toxicity and the inability to cross the blood-brain barrier .

UCLA researchers previously reported that the first-generation dopamine receptor antagonist trifluoperazine, when combined with radiation, prolonged survival in mouse models of glioblastoma, but ultimately made the mice resistant to therapy. To overcome this resistance, the team used quetiapine, a second generation dopamine receptor antagonist that not only improved the effectiveness of radiation therapy for glioblastoma, but also created metabolic susceptibility to lipid homeostasis. The discovery that the combination induced the cholesterol biosynthetic pathway enabled the team to control this process with statins.

METHOD

The team tested the approach using patient-derived glioblastoma lines provided by UCLA SPORE’s Biospecimen and Pathology Core in Brain Cancer. Quetiapine was identified in a screening of dopamine receptor antagonists for their ability to prevent the phenotypic conversion of non-tumorigenic glioblastoma cells into radiation-induced glioma-initiating cells. Atorvastatin (Lipitor) was selected for its known ability to cross the blood-brain barrier.

A HIT

While radiation alone increases glioblastoma survival to some extent, attempts to improve treatment have not been successful. The results of the study provide evidence that the use of a dopamine receptor antagonist in combination with atorvastatin and radiation may increase the survival of people with glioblastoma. Combination therapy also includes FDA-approved drugs that can be quickly translated into a clinical trial.

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AUTHORS

Lead author Dr. Frank Pajonk is Professor of Radiation Oncology at UCLA’s David Geffen School of Medicine and a member of the Jonsson Cancer Center. The main author is Dr. Kruttika Bhat, a project scientist in Pajonk’s laboratory. Other authors are Mohammad Saki, Fei Cheng, Ling He, Dr. Le Zhang, Angeliki Ioannidis, David Nathanson, Jonathan Tsang, Steven Bensinger, Dr. Phioang Leia Nghiemphu, Dr. Timothy Cloughesy, Dr. Linda Liau and Dr. Harley Kornblum. all of UCLA.

DIARY

The study was published online in the Journal of the National Cancer Institute.

FINANCING

The work was funded in part by the National Cancer Institute and the National Institutes of Health’s Brain Specialized Programs of Research Excellence (SPORE) at UCLA, which are helping advance work in the prevention, detection, and treatment of brain tumors.

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