A gene-by-gene examination of cells from one of the deadliest forms of brain cancer may have uncovered a new treatment option.
Neurosurgeon Clark Chen and his colleagues at the University of California San Diego School of Medicine decided to use a form of genetic engineering in which individuals genes in a cell are, in effect, turned off to see what impact this has on the cell.
In this case, Chen and his teams were applying this gene-silencing technique on cells from glioblastoma, one of the most aggressive and hard-to-treat malignant brain tumors. They were trying to find which genes played a key role in helping the cancerous brain cells grow and survive.
After compiling their list of genetic suspects, the U.C. San Diego researchers made an interesting discovery: Many of the genes involved in glioblastoma growth help regulate the effect of the neurochemical dopamine, they reported recently online in the journal Oncotarget.
Chen and his team made their discovery by using shRNA in a molecular engineering technique known as RNA interference. Called short-hairpin RNA by some and small-hairpin RNA by others, shRNA can keep a gene from turning the genetic blueprint encoded in its DNA into a specific protein molecule. Scientists use viruses to insert the shRNA into a target gene and block its role in the production of the protein.
“ShRNAs are invaluable tools in the study of what genes do. They function like molecular erasers,” said Chen, the vice chairman of the division of neurosurgery at the U.C. San Diego School of Medicine. “We can design these erasers against every gene in the human genome.”
Because of the similarities in the lists of genes involved in glioblastoma growth and dopamine regulation, the researchers decided to see what effect dopamine antagonist drugs would have on the brain cancer cells. They discovered these drugs have significant anti-tumor effects on glioblastoma cells grown in laboratory dishes and in lab mice.
“The anti-glioblastoma effects of these drugs are completely unexpected and were only uncovered because we carried out an unbiased genetic screen,” said Chen.
In addition to psychosis, dopamine antagonists are used to treat other disorders, including anxiety-panic and Parkinson’s disease and to control nausea and vomiting and already have a stamp of approval from the U.S. Food and Drug Administration.
“First, these drugs are already FDA-cleared for human use in the treatment of other diseases, so it is possible these drugs may be re-purposed for glioblastoma treatment, thereby bypassing years of pre-clinical testing,” said Bob Carter, chairman of the U.C. San Diego School of Medicine division of neurosurgery.
The FDA would still have to approve the clinical use of dopamine antagonists to treat glioblastoma.
Dopamine antagonists, according to Carter, have another big thing going for them: They are able to make it through the blood-brain barrier.
The blood-brain barrier is formed by cells within tiny blood vessels known as capillaries It keeps potentially harmful things such as bacteria and most large molecules out of the brain, only letting in things brain cells need to survive, such as oxygen and nutrients.
On the negative side, the blood-brain barriers blocks roughly 9 out of 10 anti-cancer drugs, limiting their use in treating brain malignancies.
Chen is working with the neuro-oncology team at the U.C. San Diego Moores Cancer Center on a study to test the ability of dopamine antagonists to treat glioblastoma in humans.
The Sontag, Burroughs Wellcome, Kimmel and Forbeck foundations funded Chen’s research.