Glioblastoma (GBM) is the most lethal brain tumour, with a median survival rate of merely 12-16 months after diagnosis.

Despite surgical, radiation and chemotherapy treatments, the two-year survival rate for GBM patients is less than 10%.

Two major challenges hinder effective GBM treatment:

• the limited penetration of anti-tumour drugs into GBM tissues because of the blood-brain-barrier.
• the rapid development of resistance by GBM cells to almost all treatments.

Researchers with The Ohio State University Comprehensive Cancer Centre – Arthur G. James and Richard J. Solove Research Institute are trying to resolve these two paramount issues to improve outcomes.

“In a major finding with our study, we discovered combining the brain-penetrating antipsychotic drug pimozide with a clinically investigative glutamine metabolism inhibitor, CB-839, can overcome tumour resistance and effectively suppress GBM growth,” said study lead author Deliang Guo, PhD, the founding director of the Centre for Cancer Metabolism.

Guo also is the Urban and Shelly Meyer Professor of Cancer Research with the OSUCCC – James Translational Therapeutics Programme and a professor at The Ohio State University College of Medicine.

Study findings are published online in the journal Cell Reports Medicine.

The study involved both humans and mice.

Researchers analysed 223 glioma patient samples and identified the previously unknown connection between the glutamine transporter ASCT2 protein and a key lipogenic regulator, SREBP-1.

They used a preclinical mouse GBM model to validate this mechanistic link.

They found GBM cells increase glutamine consumption and lipid production at the same time to promote rapid tumour growth.

“Specifically, we have observed that pimozide effectively curbs the release of cholesterol and fatty acids from lipid droplets and lipoprotein via inhibition of lysosomal function,” Guo said.

“These effects are expected to starve tumour cells of these crucial lipid building blocks. Nevertheless, pimozide treatment alone does not yield the desired efficacy against glioblastoma.”

The investigation found that GBM’s resistance to treatment with pimozide is attributed to its upregulation of glutamine uptake and consumption.

The research team believes that their findings will have a significant and lasting impact across many areas including cancer biology, metabolism, signalling transduction and treatment models.

“Our research provides compelling evidence for this innovative combination for glioblastoma treatment,” said study first author Yaogang Zhong, PhD, a researcher with the Department of Radiation Oncology and Centre for Cancer Metabolism at OSUCCC-James.

“This new strategy may also hold promise for treating other cancers that heavily rely on glutamine and lipids, broadening its potential impact beyond this deadly brain cancer.”

Source: Ohio State University Wexner Medical Center