Glioblastoma treatment shows promise in mouse study

Memorial Sloan Kettering Cancer Center-led researchers have identified a small molecule called gliocidin that kills glioblastoma cells without damaging healthy cells, potentially offering a new therapeutic avenue for this aggressive brain tumor.

Glioblastoma remains one of the most lethal primary brain tumors, with current therapies failing to significantly improve patient survival rates. Glioblastoma is difficult to treat for several reasons. The tumor consists of many different types of cells, making it difficult for treatments to target them all effectively.

There are few genetic changes in the cancer for drugs to target, and the tumor creates an environment that weakens the body’s immune response against it. Even getting medications near targets in the brain is challenging because the protective blood-brain barrier blocks entry for most potential drug treatments.

In a study, “Gliocidin is a nicotinamide-mimetic prodrug that targets glioblastoma,” published in Nature, the team conducted a high-throughput compound screening of more than 200,000 chemical compounds to identify treatment potential in mouse model glioblastoma cells. Gliocidin emerged as a compound selectively toxic to glioblastoma cells while sparing healthy cells.

To investigate gliocidin’s mechanism of action, researchers performed a genome-wide CRISPR–Cas9 knockout screen to identify genes that influence gliocidin’s effectiveness against glioblastoma cells.

They discovered that gliocidin takes advantage of a specific weakness in the glioblastoma molecular machinery by indirectly blocking an enzyme known as inosine monophosphate dehydrogenase 2 (IMPDH2). This inhibition reduces intracellular guanine nucleotide levels, causing nucleotide imbalance, DNA replication stress, and ultimately resulting in tumor cell death.

Gliocidin begins as an inactive prodrug substance that the body transforms into its active form, gliocidin–adenine dinucleotide (GAD), using the enzyme nicotinamide nucleotide adenylyltransferase 1 (NMNAT1). Once activated, GAD binds to IMPDH2, changing its shape and blocking its regular interaction activity.

In vivo experiments in mice showed that gliocidin can penetrate the blood-brain barrier, effectively slow tumor growth, and extend the survival of the mice. When combined with the chemotherapy drug temozolomide (which induces NMNAT1 expression), the treatment significantly improved survival rates.

Treated mice did not lose weight, blood tests and examinations of major organs found no significant issues, and the mice’s immune systems remained healthy.

Safe and effective treatment in mice introduces gliocidin as a promising prodrug with the potential to improve survival outcomes for patients with glioblastoma, making it a clear candidate for future clinical trials.

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