Glioblastoma is the most aggressive and lethal form of brain tumor, with a median survival time of around 15 months. The current standard of care involves surgery, radiation, and some combination of chemotherapy. Drugs that are effective against brain tumors are difficult to find, as many cancer drugs often cannot cross the blood-brain barrier to reach the brain. Scientists have been searching intensively for better therapeutics that can reach the brain and eliminate the tumor. Now, researchers have uncovered in cell cultures and mice that an antidepressant called vortioxetine—that is capable of crossing the blood-brain barrier—may help combat glioblastomas.
The research is published in Nature Medicine in an article titled, “High-throughput identification of repurposable neuroactive drugs with potent anti-glioblastoma activity,” and led by ETH Zurich professor Berend Snijder, PhD.
Snijder’s postdoc and lead author of the study, Sohyon Lee, PhD, found the drug using pharmacoscopy, a special screening platform that the researchers have developed at ETH Zurich. In this study, the ETH Zurich researchers worked closely with colleagues from various hospitals, in particular with the group under neurologists Michael Weller, MD, and Tobias Weiss, MD, at the University Hospital Zurich (USZ).
ETH Zurich researchers can simultaneously test hundreds of active substances on living cells from human cancer tissue with pharmacoscopy. Their study focused on neuroactive substances that cross the blood-brain barrier, such as antidepressants, Parkinson’s medication, and antipsychotics. In total, the research team tested up to 130 different agents on tumor tissue from 40 patients.
To determine which substances have an effect on the cancer cells, the researchers used imaging techniques and computer analysis. Previously, Snijder and his team had used the pharmacoscopy platform only to analyze blood cancer and derived treatment options from this. Glioblastomas are the first solid tumors that they have systematically investigated using this method with a view to using existing drugs for new purposes.
For the screening, Lee analyzed cancer tissue from patients who had recently undergone surgery at USZ. The ETH Zurich researchers then processed this tissue in the laboratory and screened it on the pharmacoscopy platform. Two days later, the researchers obtained results showing which agents worked on the cancer cells and which did not.
The results made it clear that some, but not all, of the antidepressants tested were unexpectedly effective against the tumor cells. These drugs worked well when they quickly triggered a signaling cascade, which is important for neuronal progenitor cells, but also suppresses cell division. Vortioxetine proved to be the most effective antidepressant.
The ETH Zurich researchers also used a computer model to test over a million substances for their effectiveness against glioblastomas. They found that the joint signaling cascade of neurons and cancer cells plays a decisive role and explains why some neuroactive drugs work while others don’t.
In the last step, researchers at the University Hospital Zurich tested vortioxetine on mice with a glioblastoma. The drug also showed good efficacy in these trials, especially in combination with the current standard treatment.
The group of ETH Zurich and USZ researchers is now preparing two clinical trials. In one, glioblastoma patients will be treated with vortioxetine in addition to standard treatment (surgery, chemotherapy, radiation). In the other, patients will receive a personalized drug selection, which the researchers will determine for each individual using the pharmacoscopy platform.
“The advantage of vortioxetine is that it is safe and very cost-effective,” explained Michael Weller, MD, professor at the University Hospital Zurich, director of the department of neurology, and co-author of the study. “As the drug has already been approved, it doesn’t have to undergo a complex approval procedure and could soon supplement the standard therapy for this deadly brain tumor.” He hopes that oncologists will be able to use it soon.
However, he cautions patients and their relatives against obtaining vortioxetine themselves and taking it without medical supervision. “We don’t yet know whether the drug works in humans and what dose is required to combat the tumor, which is why clinical trials are necessary. Self-medicating would be an incalculable risk.”
Snijder, too, warns against rushing to use the antidepressant on glioblastomas: “So far, it’s only been proven effective in cell cultures and in mice.”
Although their research is still in the early stages, Snijder believes that the study achieved an ideal result: “We started with this terrible tumor and found existing drugs that fight against it. We show how and why they work, and soon we’ll be able to test them on patients.” If vortioxetine is found to be effective, this will be the first time in recent decades that an active substance has been found to improve the treatment of glioblastoma.
