Neuroactive drugs show promising anti-glioblastoma effects in preclinical trials

Researchers find that the antidepressant vortioxetine may offer new hope for glioblastoma patients by crossing the blood-brain barrier and significantly reducing tumor size in preclinical models.

Current treatment strategies for glioblastoma

Glioblastoma is an incurable and fatal type of brain cancer, with about 50% of patients dying within twelve months of diagnosis. The life expectancy of glioblastoma patients can be extended through radiation, chemotherapy, or surgical interventions.

Many drugs that are used to treat cancer cannot cross the blood-brain barrier (BBB), thus limiting the utility of these agents in treating brain tumors like glioblastoma. Targeted therapies have been associated with limited success in the treatment of glioblastoma due to the lack of clinically predictive patient model systems, as well as the presence of treatment-resistant glioblastoma stem cells (GSCs).

Recent studies investigating the pathophysiology of glioblastoma have reported synaptic integration of cancer cells into neural circuits, stemness signatures resembling neural development, and the modulation of specific neurotransmitter pathways in the tumor microenvironment (TME). These characteristics may reflect vulnerabilities of glioblastoma cells, which may be therapeutically relevant, particularly when investigating the potential repurposing of existing ‘neuroactive’ drugs (NADs).

The lack of effective treatments for managing glioblastoma emphasizes the importance of identifying neurotherapeutic vulnerabilities that can guide future drug discovery in this field. To date, the anti-cancer activity of most NADs has not been evaluated for the treatment of glioblastoma.

About the study

Pharmacoscopy is an ex vivo image-based drug screening approach that has been validated in functional precision medical trials assessing the effects of novel agents in the treatment of hematological malignancies. In the current study, researchers used pharmacoscopy to simultaneously test the in vitro and in vivo efficacy of both neuroactive and oncology drug (ONCD) libraries against glioblastoma patient samples.

The neuroactive drug library consisted of drugs capable of crossing the BBB that are currently approved for the treatment of neurological diseases like Alzheimer’s disease, depression, and schizophrenia. Comparatively, the ONCD drug library consisted of conventional cancer treatments, such as cyclin-dependent kinase (CDK) and receptor tyrosine kinase (RTK) inhibitors.

A total of 130 different agents were used to treat tumor tissues isolated from 27 patients who recently underwent surgery at the University Hospital Zurich. Imaging techniques and computer analysis were used to identify drugs that influenced cancer cells.

Study findings

Several ONCDs were capable of penetrating the BBB, which included elesclomol, osimertinib, and regorafenib.

Certain patient characteristics increased the sensitivity of their tumor cells to specific ONCDs. For example, age was associated with greater sensitivity to elesclomol, tumor samples obtained from patients with TP53 mutations were more sensitive to CDK4/6 inhibitor abemaciclib, and patients with the loss of rearranged during transfection (RET) copies were more sensitive to pazopanib.

Innovative machine learning approach: The researchers utilized the COSTAR model, analyzing over one million compounds, to predict which drugs target shared glioblastoma vulnerabilities and enhance treatment efficacy.

Fifteen NADs exhibited anti-glioblastoma activity, with vortioxetine, an antidepressant, inducing significant ex vivo efficacy in about 67% of patient samples. Other potent NADs were paroxetine, fluoxetine, and brexpiprazole.

Higher sertindole sensitivity was observed among patients with fibroblast growth factor receptor 2 (FGFR2) copy number loss. Moreover, higher ex vivo sensitivity to brexpiprazole was observed in male patients.

A machine learning approach was designed to search for the convergence of secondary drug targets analyzed by regularized regression (COSTAR). This model tested over one million substances for their effectiveness against glioblastoma and documented neuroactive convergence on activating protein 1 (AP-1)/BTG-driven glioblastoma suppression. The joint signaling cascade of cancer and neural cells is important and key to elucidating the selective therapeutic efficacy of certain NADs.

Vortioxetine was consistently the most effective NAD in vivo, especially in combination with the current standard treatment. Furthermore, the survival benefits associated with vortioxetine treatment were significant and similar to those of alkylating agent temozolomide (TMZ).

Magnetic resonance imaging (MRI) scans of transplanted mice showed a significant reduction in tumor size post-treatment with vortioxetine. In vitro, vortioxetine reduced glioblastoma growth, clonogenic survival, and invasiveness.

Consistent with previously reported findings, paliperidone and citalopram were not associated with any survival benefit. The ineffectiveness of citalopram suggests that anti-glioblastoma efficacy is not conferred solely by serotonin modulation.

Conclusions

Diverse NADs, particularly the antidepressant vortioxetine, led to rapid glioblastoma cell death.

Although the study findings are promising, vortioxetine should not be used in the treatment of glioblastoma without proper medical supervision, as its efficacy has only been proven in vitro and in mice. Thus, future clinical studies are needed to evaluate the therapeutic efficacy of vortioxetine in human glioblastoma patients.

Journal reference:

• Lee, S., Weiss, T., Buhler, M., et al. (2024) High-throughput identification of repurposable neuroactive drugs with potent anti-glioblastoma activity. Nature Medicine; 1-13. doi:10.1038/s41591-024-03224-y