Antidepressant Shows Promise in Treating Deadly Brain Tumor!

News

Antidepressant Shows Promise in Treating Deadly Brain Tumor!

Antidepressant Shows Promise in Treating Deadly Brain Tumor!

Glioblastoma is the most lethal primary brain cancer, with extremely limited treatment options.

Its progression is influenced by various factors, including genetic components and the tumor microenvironment.

Despite growing understanding of glioblastoma, the only FDA-approved first-line drug, temozolomide (TMZ), offers only a modest increase in median survival, highlighting the urgent need for new treatment strategies.

A promising new approach is to focus on the neurobiological characteristics of glioblastoma, such as exploring markers related to neurodevelopment, the link between cancer cells and neural circuits, and the role of neurotransmitter regulation in the tumor microenvironment. With this approach in mind, researchers are turning to approved neuroactive drugs (NADs), which can cross the blood-brain barrier and are already used to treat neurological conditions. These drugs might hold potential for treating glioblastoma as well.

A research team led by Berend Snijder at the University of Zurich has discovered through a drug-screening platform that vortioxetine, an approved neuroactive drug, shows significant anti-glioblastoma activity in vitro. In mouse models, vortioxetine, when combined with temozolomide or lomustine, extended survival by 20%-30% compared to chemotherapy alone. However, the study also noted that some patients may not benefit from vortioxetine, providing insights into future patient stratification strategies.

This study was recently published in the journal Nature Medicine.

Antidepressant Shows Promise in Treating Deadly Brain Tumor!

The drug-screening platform, PCY, developed by Snijder’s team, had previously been validated for its performance in studies targeting blood malignancies. This study marks the first time PCY has been applied to drug discovery in hard-to-treat solid tumors.

To identify existing drugs that could be repurposed for glioblastoma treatment, researchers used PCY to test 67 neuroactive drugs (NADs) on surgical samples from dozens of glioblastoma patients. These drugs, including those approved for treating depression, schizophrenia, and Alzheimer’s disease, were tested alongside 65 anti-cancer drugs, such as CDK (cyclin-dependent kinase) inhibitors and RTK (receptor tyrosine kinase) inhibitors.

Results showed that 13.5% of the drugs demonstrated significant anti-tumor activity. The top four included anti-glioblastoma drugs: Elesclomol (oxidative stress inducer), Sorafenib (tyrosine kinase inhibitor), Pralsetinib (RTK inhibitor), and Ribociclib (CDK inhibitor).

Surprisingly, the fifth-ranked drug was vortioxetine, an antidepressant that showed strong in vitro efficacy in 66.7% of patient samples. Other notable neuroactive drugs included the selective serotonin reuptake inhibitors (SSRIs) paroxetine (ranked 15) and fluoxetine (ranked 19), as well as the antipsychotic brexpiprazole (ranked 17).

Researchers employed a machine learning model called COSTAR to predict the in vitro efficacy of neuroactive drugs in glioblastoma. COSTAR analyzed the biological activity of drugs and their targets, revealing that the neuroactive drugs screened by PCY primarily acted through targets like BTG2 and AP-1, suggesting these pathways could be key in glioblastoma treatment.

Further investigation into the mechanism of vortioxetine revealed that it rapidly activates calcium signaling pathways, triggering a series of transcriptional responses that significantly increase the expression of AP-1 factors. The upregulation of AP-1 is closely associated with tumor cell apoptosis. Vortioxetine also promotes the expression of tumor suppressor genes BTG1 and BTG2 through AP-1 activation, inhibiting the proliferation and growth of glioblastoma cells. Moreover, vortioxetine not only induces direct tumor cell death but also influences tumor growth and progression by regulating the expression of neuroactive genes.

In two xenograft glioblastoma mouse models, researchers evaluated vortioxetine’s anti-tumor effects in vivo. The results showed consistent tumor reduction across four independent trials, with vortioxetine monotherapy significantly decreasing tumor size after 15 days of treatment and improving survival rates. Its anti-tumor effect was comparable to temozolomide, the standard chemotherapy for glioblastoma.

When combined with temozolomide or lomustine, vortioxetine further extended survival, increasing median survival by 20%-30% compared to monotherapy. In 25% of the mice (4 out of 12), long-term survival was achieved.

Finally, the researchers found that glioblastoma patients with low Ki67 levels and without EGFR mutations were the least likely to benefit from vortioxetine. This discovery provides a basis for future stratified patient treatment, helping identify those who may benefit most from vortioxetine, optimizing its clinical application.

These findings indicate that neuroactive drugs identified through PCY hold significant potential for clinical translation. Vortioxetine’s efficacy in vitro suggests it could be a viable candidate for glioblastoma treatment, especially when combined with existing chemotherapy regimens for improved outcomes.