A small molecule that penetrates the brain offers a chance at curing an aggressive brain tumor

Researchers have discovered gliocidin, an agent that penetrates the blood-brain barrier, impacts the unique metabolic vulnerability of glioblastoma, suggesting a promising therapeutic strategy and increased survival, according to a study in preclinical models.

In a recent study published in Nature, a team led by scientists at Memorial Sloan Kettering Cancer Center examined the effects of gliocidin on glioblastoma, an aggressive form of brain tumor.

The study showed that gliocidin targets specific cellular pathways, selectively killing glioblastoma cells without harming normal cells. Moreover, the compound is able to penetrate the blood-brain barrier, highlighting its potential as a treatment for glioblastoma.

Glioblastoma is one of the deadliest forms of brain cancer, known for its resistance to standard therapies. Despite significant advances in current cancer therapies – immunotherapy and targeted therapies have had minimal success in improving survival rates in glioblastoma. Resistance to treatment is thought to be due to a number of properties unique to glioblastoma, such as complex cellular heterogeneity and the ability to be immune compromised.

In this study, scientists sought to find a compound that could selectively target glioblastoma cells. A high-throughput chemical screening of more than 200,000 compounds was performed using glioblastoma cells derived from genetically engineered mouse models. Compounds toxic to normal replicating cells were excluded from further development. As a result of screening, gliocidin, which has selective toxicity against glioblastoma cells, was selected as a promising candidate.

Pharmacokinetics and biodistribution studies in animal models were used to determine the ability of gliocidin to cross the blood-brain barrier and maintain an effective concentration in the brain. The researchers used mouse models carrying glioblastoma for this purpose. Administration of the drug was optimized by intraperitoneal injection, and tissue analysis was used to confirm its presence in the brain.

The study showed that gliocidin effectively targets glioblastoma cells by exploiting specific metabolic abnormalities in cancer cells.

In addition, biochemical assays confirmed that gliocidin selectively disrupts guanine nucleotide synthesis in glioblastoma cells without affecting normal cells. The study demonstrated this specificity in several glioblastoma cell lines and patient-derived xenograft models. In addition, pharmacokinetic studies have shown that gliocidin successfully crosses the blood-brain barrier and accumulates in sufficient amounts in the brain to provide a prolonged effect of the compound on cancer cells.

In addition, in vivo studies in mice bearing glioblastoma showed that gliocidin monotherapy significantly suppressed tumor progression. When combined with temozolomide, the standard treatment for glioblastoma, gliocidin had a synergistic effect, resulting in greater tumor shrinkage and improved survival rates. Analysis of tumor samples obtained from treated mice showed that the combination therapy enhanced glioblastoma cell death by targeting both proliferative and non-proliferative tumor cells.

Overall, the results suggest that gliocidin is able to selectively kill glioblastoma cells by disrupting critical pathways of nucleotide synthesis. Its ability to penetrate the brain emphasizes the potential of this compound as a promising treatment for glioblastoma.

In addition, the increased efficacy observed when gliocidin was used in combination with temozolomide further supports the potential of gliocidin as a future therapeutic approach for the treatment of patients with glioblastoma.