A common antidepressant, fluoxetine (commonly known as Prozac), appears to target glioblastoma, at least in lab mice, according to a new study.
Glioblastoma is a difficult to treat, often fatal brain cancer.
Stanford University pathologist Paul Mischel, who has spent years studying glioblastoma, and postdoctoral researcher Junfeng Bi, have made the surprising discovery of the link between Prozac and glioblastoma.
Additionally, actual data from electronic medical records suggests that glioblastoma patients prescribed Prozac along with standard treatment for the disease survived longer.
The results appear in Cell reports. While much more research needs to be done on whether the drug works the same way in humans, the possibility is enticing.
“Glioblastoma is a terrible cancer,” says Mischel. “It’s the most common malignant brain cancer in adults, but we have no way of catching it early and treatments are often ineffective. “
The challenge of fighting brain cancer
The unique makeup of the brain is part of what makes these cancers difficult to treat. It is sequestered from the rest of the body by the blood-brain barrier, which protects valuable nerve cells from potential harmful agents circulating in the blood.
“Patients who received Prozac, as well as standard glioblastoma care, lived much longer than the control group. “
But this barrier also prohibits the entry of many drugs – another hurdle to overcome when designing drugs to target brain cancers. Finally, glioblastomas are known to have many copies of genes associated with cancer, including one called the epidermal growth factor receptor, or EGFR.
“In most cancers EGFR is mutated to become more active, but in glioblastomas the EGFR gene is instead amplified multiple times,” says Mischel. “But previous work in my lab has shown that direct targeting of these amplifications has not been successful.”
Mischel and Bi knew that the balance of cholesterol and a class of fats called lipids is often severely disrupted in glioblastoma cells. They also knew that these lipids are important in EGFR signaling. After a series of deductions, they focused on a lipid called sphingolipid as potentially important in the growth and survival of glioblastoma.
They found that people with glioblastomas whose cancers produced high levels of an enzyme involved in sphingolipid metabolism called SMPD1 had a significantly shorter lifespan than patients whose cancers expressed lower levels of the enzyme. .
Glioblastoma tumors have “melted”
Mischel and Bi then searched the scientific literature for compounds capable of inhibiting SMPD1 and also crossing the blood-brain barrier.
“We almost fell out of our chairs when we saw that fluoxetine, or Prozac, was achieving both of these goals,” Mischel said. “It is known to be harmless, it can enter the brain and inhibit SMPD1. And when we administered Prozac in a safe dose to mice with human glioblastomas, the levels of the oncogene EFGR dropped dramatically and the tumors melted and did not come back. It’s something we’ve never seen before.
Since fluoxetine is widely used as an antidepressant, Mischel and Bi questioned whether there was any evidence of an effect on glioblastoma. So they looked at electronic medical records from a large insurance claims database to identify people with glioblastomas who had also taken fluoxetine during their illness. Because glioblastoma is, fortunately, a relatively rare disease, the sample size was small. But the data they found was intriguing.
“We found that the patients who received Prozac, along with standard care for glioblastoma, lived much longer than the control group,” says Mischel.
The researchers plan to partner with the National Brain Tumor Society to design a clinical trial to test the effect of fluoxetine in people with glioblastoma.
“It’s a drug that is on the shelves of every drugstore, and it’s known to be safe. We believe this is about to be tested in patients very soon, ”said Mischel.
The National Brain Tumor Society, which also helped fund this study, offers a personalized support and navigation service with a team with extensive experience navigating brain tumor treatment options and issues. Patients and families who have questions about this study or others can email the Brain Tumor Society team at firstname.lastname@example.org.
Source: Stanford University