Antidepressant could help fight glioblastoma brain tumors

Summary: Researchers have discovered in laboratory tests and on mice that the antidepressant vortioxetine is effective in fighting glioblastoma, a deadly brain tumor. Already approved by the FDA, this drug crosses the blood-brain barrier and, when combined with standard therapy, could potentially improve the treatment of glioblastoma patients.

The study, which used a screening platform, identified vortioxetine as the top candidate. Clinical trials are currently planned. Although the drug is promising, experts warn against self-medication as human trials are still needed.

Key data:

• Vortioxetine penetrates the blood-brain barrier and fights glioblastomas in laboratory tests.
• Researchers found that antidepressants are surprisingly effective against tumor cells.
• Clinical trials are being prepared to test the effects of vortioxetine in patients with glioblastoma.

Source: ETH Zurich

Glioblastoma is a particularly aggressive brain tumor that is currently incurable. Cancer doctors can extend the life expectancy of patients through surgery, radiation, chemotherapy or surgical interventions. Nevertheless, half of patients die within twelve months of diagnosis.

Drugs that are effective against brain tumors are difficult to find because many cancer drugs often cannot cross the blood-brain barrier to reach the brain. This limits the choice of possible treatments. Neuro-oncologists have therefore been searching intensively for some time for better drugs that can reach the brain and eliminate the tumor.

Researchers led by ETH professor Berend Snijder have now found a substance that effectively combats glioblastomas, at least in the laboratory: an antidepressant called vortioxetine. The inexpensive drug, which has already been approved by authorities such as the American FDA and Swissmedic, is able to overcome the blood-brain barrier, as scientists know.

Snijder's postdoc and lead author of the study, Sohyon Lee, found out using pharmacoscopy, a special screening platform that researchers have developed in recent years at ETH Zurich.

The study results were published in the journal Natural medicine.

For the study, the ETH researchers worked closely with colleagues from various hospitals, in particular with the group of neurologists Michael Weller and Tobias Weiss at the University Hospital Zurich (USZ).

Test hundreds of substances simultaneously

Using pharmacoscopy, ETH researchers can test hundreds of active substances simultaneously on living cells from human cancer tissue. The focus of their study was primarily on neuroactive substances that pass through the blood-brain barrier, such as antidepressants, Parkinson's drugs and antipsychotics. In total, the research team tested up to 130 different active substances on the tumor tissue of 40 patients.

To find out which substances affect the cancer cells, the researchers used imaging techniques and computer analysis. Until now, Snijder and his team had only used the pharmacoscopy platform to analyze blood cancer and derive treatment options from it. Glioblastomas are the first solid tumors that they have systematically studied using this method in order to use existing drugs for new purposes.

For the screening, Lee analyzed fresh cancer tissue from patients who had recently undergone surgery at the University Hospital of Zurich. The ETH researchers then processed this tissue in the laboratory and examined it on the pharmacoscopy platform. Two days later, the researchers received results that showed which active substances were effective against the cancer cells and which were not.

Antidepressants surprisingly effective

The results made it clear that some, but not all, of the antidepressants tested were unexpectedly effective against the tumor cells. These drugs worked particularly well when they quickly set in motion a signaling cascade that is important for neuronal precursor cells, but also inhibits cell division. Vortioxetine proved to be the most effective antidepressant.

The ETH researchers also used a computer model to test over a million substances for their effectiveness against glioblastomas. They found that the shared signaling cascade of nerve cells and cancer cells plays a crucial role and explains why some neuroactive drugs work and others do not.

In the final step, researchers at the University Hospital of Zurich tested vortioxetine on mice with glioblastoma. In these tests, too, the drug showed good efficacy, especially in combination with the current standard therapy.

The group of researchers from ETH Zurich and USZ is now preparing two clinical trials. In one of them, glioblastoma patients will be treated with vortioxetine in addition to standard treatment (surgery, chemotherapy, radiation). In the other, the patients will receive a personalized drug selection that the researchers will determine for each individual using the pharmacoscopy platform.

Drug widely available and inexpensive

“The advantage of vortioxetine is that it is safe and very cost-effective,” says Michael Weller, professor at the University Hospital Zurich, director of the Department of Neurology and co-author of the study.

“Since the drug is already approved, it does not have to go through a complex approval process and could soon complement the standard therapy for this deadly brain tumor.” He hopes that oncologists will soon be able to use it.

However, he warns patients and relatives against getting vortioxetine themselves and taking it without medical supervision. “We do not yet know whether the drug works in humans and what dose is needed to fight the tumor, which is why clinical trials are necessary. Self-medication would be an incalculable risk.”

Snijder also warns against using the antidepressant too quickly to treat glioblastomas: “So far, its effectiveness has only been proven in cell cultures and in mice.”

Still, he believes this study has achieved an ideal result. “We started with this terrible tumor and found existing drugs that fight it. We are showing how and why they work, and soon we will be able to test them on patients.”

If vortioxetine proves effective, it would be the first time in decades that a drug has been found that improves the treatment of glioblastoma.

About this research news on brain tumors and neuropharmacology

Author: Berend Snijder
Source: ETH Zurich
Contact: Berend Snijder – ETH Zurich
Picture: The image is from Neuroscience News.

Original research: Open access.
“High-throughput identification of reusable neuroactive drugs with potent anti-glioblastoma activity” by Berend Snijder et al. Natural medicine

Abstract

High-throughput identification of reusable neuroactive drugs with potent anti-glioblastoma activity

Glioblastoma, the most aggressive primary brain tumor, has a dismal prognosis, but systemic treatment is limited to DNA-alkylating chemotherapies. Exploring the neurodevelopmental and neurophysiological vulnerabilities of glioblastoma may provide new therapeutic strategies.

To this end, we systematically screened reusable neuroactive drugs in surgical specimens from glioblastoma patients using a clinically consistent and single-cell-resolved platform.

By profiling more than 2,500 ex vivo drug responses in 27 patients and 132 drugs, cross-class neuroactive drugs with potent anti-glioblastoma efficacy were identified and validated in various model systems.

Interpretable molecular machine learning of drug target networks revealed neuroactive convergence in AP-1/BTG-driven glioblastoma suppression and enabled expanded in silico screening of more than 1 million compounds with high fidelity in patient validation.

Deep multimodal profiling confirms Ca²⁺-controlled AP-1/BTG signaling pathway induction as a neuro-oncological glioblastoma vulnerability, embodied by the antidepressant vortioxetine, which shows a synergistic effect with current standard chemotherapies in vivo.

These findings provide an actionable framework for the treatment of glioblastoma based on its neuronal etiology.