Antipsychotic medications offer hope against glioblastoma

Researchers have discovered that FDA-approved antipsychotic drugs possess tumor-killing activity against the most aggressive form of primary brain cancer, glioblastoma.

The team of scientists from the University of California, San Diego School of Medicine, led by principal investigator Clark C. Chen, MD, PhD, used a technology platform called shRNA to test how each gene in the human genome contributed to glioblastoma growth.

ShRNA stands for small hairpin or short hairpin RNA, and this type of RNA sequence makes a tight hairpin turn that can silence target gene expression by RNA interference. The discovery that led to the shRNA technology won the Nobel Prize in Physiology/Medicine in 2006.

"ShRNAs are invaluable tools in the study of what genes do. They function like molecular erasers," said Chen. "We can design these 'erasers' against every gene in the human genome. These shRNAs can then be packaged into viruses and introduced into cancer cells. If a gene is required for glioblastoma growth and the shRNA erases the function of that gene, then the cancer cell will either stop growing or die."

Chen said that one surprising finding is that many genes required for glioblastoma growth are also required for dopamine receptor function. Dopamine is a small molecule that is released by nerve cells and binds to the dopamine receptor in surrounding nerve cells, enabling cell communication.

Abnormal dopamine regulation is associated with Parkinson's disease, schizophrenia, and attention-deficit/hyperactivity disorder. Because of the importance of dopamine in these diseases, drugs have been developed to neutralize the effect of dopamine, called dopamine antagonists.

Following clues unveiled by their shRNA study, Chen and his team tested the effects of dopamine antagonists against glioblastoma and found that these drugs exert significant antitumor effects both in cultured cells and mouse models. These effects are synergistic when combined with other anti-glioblastoma drugs in terms of halting tumor growth.

"The antiglioblastoma effects of these drugs are completely unexpected and were only uncovered because we carried out an unbiased genetic screen," said Chen. This study was published online in Oncotarget on March 7, 2014.

"On the clinical front, the finding is important for two reasons," said Bob Carter, MD, PhD, chairman of UC San Diego, School of Medicine, Division of Neurosurgery. "First, these drugs are already FDA-cleared for human use in the treatment of other diseases, so it is possible these drugs may be repurposed for glioblastoma treatment, thereby bypassing years of preclinical testing. Second, these drugs have been shown to cross the blood-brain barrier, a barrier that prevents more than 90% of drugs from entry into the brain."

Chen is now working with the UC San Diego Moores Cancer Center Neuro-Oncology team to translate his findings into a clinical trial.

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