A group of scientists, led by Dr. Clark C. Chen of the University Of California San Diego School Of Medicine, are reporting on their discovery that an FDA-approved antipsychotic drug has tumor-fighting activity against glioblastoma, one of the most highly malignant of human cancers, with most patients succumbing to the disease within two years of diagnosis. Worse, because this particular cancer does not grow into a discrete tumor, the glioblastomas are inoperable. Approximately 10,000 cases are diagnosed each year in the US.
The scientists utilized a technology called “shRNA” (for short hairpin Ribonucleic Acids) to look at each gene in the entire human collection and study its role in the growth of the glioblastoma. ShRNAs function like “molecular erasers,” according to Dr. Chen, enabling scientists to completely eradicate the activity of specific genes, one at a time, to get a sense of what the genes do. Researchers who discovered the action of shRNAs were awarded the Nobel Prize in Physiology and Medicine in 2006.
It’s a very simple assay. ShRNAs can be inserted into cancer cells by means of viruses that have been repurposed for delivery of genetic material. If the gene that is erased by the shRNA is essential for the survival of the tumor cell, the tumor cell will die.
As occasionally happens in science, the researchers stumbled across something unexpected. Dr. Chen found that many of the genes that affect the growth of glioblastoma cells are also required for the function of a dopamine receptor called D2. Dopamine may be familiar to some as a small neurotransmitter – a molecule released at one end of a neuron that makes its way across a synapse (a junction between two neurons) and binds to a receptor specific for dopamine on the other side of the neuronal junction. Disorders involving dysregulation of dopamine are common, and include Parkinson’s disease (PD), Schizophrenia, and Attention Deficit Hyperactivity Disorder (ADHD). To combat these diseases, drugs that oppose the action of dopamine (also known as dopamine “antagonists” – they “antagonize” the dopamine function, get it?) have been developed. One dopamine antagonist in particular, called haloperidol, has been in use for decades as an antipsychotic drug to treat symptoms of schizophrenia.
Thinking logically, Dr. Chen’s team decided to see if the antipsychotic drug that affected the function of the dopamine receptor would also have tumor-fighting activity against the glioblastoma. Happily, they found the antipsychotic drug had significant tumor-fighting capabilities, not just on glioblastoma cells in culture, but also in genetically engineered mice. Even better, the tumor-fighting effect was stronger when the haloperidol was combined with other anti-glioblastoma drugs.
Dr. Bob Carter, MD, PhD, chairman of UCSD School of Medicine neurosurgery division, commented on the finding, calling it “important” for two reasons. First, since the antipsychotic drug tested in this experiment is already FDA-approved as a psychotherapeutic, its tumor-fighting activity against glioblastoma could be cleared for use without having to go through years of pre-clinical studies. Second, haloperidol is already known to cross the blood-brain barrier, which normally presents a formidable obstacle to potential therapeutic drugs, as it blocks more than 90 percent of the putative treatments from entering the brain. Future directions for Dr. Chen include setting up clinical trials with the UCSD Moores Cancer Center Neuro-Oncology team.
By Laura Prendergast