International Business Department           Liu Bojia           November 25, 2024

  Glioblastoma is a highly aggressive malignant brain tumour with a survival time of approximately 10-13 months after diagnosis and a 5-year survival rate of only 5%-10%. With the development of targeted therapies and cellular therapies, some tumour types have gained new treatment options, but glioblastoma is particularly ‘hardy’, and clinical data show that these two types of therapies have little or no positive impact on the survival of glioblastoma patients. Conventional therapies, such as surgery, chemotherapy and radiotherapy, have also not been effective, and scientists urgently need to find a new treatment to save the lives of glioblastoma patients.

  Just this week, a paper in the journal Nature showcased a molecule called Gliocidin, which stands for glioblastoma-killing hormone (a similar grouping would be bactericidin). In the past, the blood-brain barrier has been a major barrier for drugs to get inside the brain to do their job, but the authors found that Gliocidin not only possesses strong blood-brain barrier penetration, but can also precisely target tumour cells to do its job. Its ability to promote cell stress and death by inhibiting glioblastoma DNA and RNA production. This efficient brain penetration and tumour specificity also gives Gliocidin an extremely broad application prospect.

  According to the paper, Gliocidin is deservedly a ‘one-in-a-million’ molecule, which the authors found through high-throughput screening of a library of 200,000 compounds based on glioblastomas of multiple oncogenic genotypes. in cellular tests, Gliocidin was both effectively kill glioblastoma without affecting the survival of normal embryonic fibroblasts.

  Unlike conventional drugs that block mitosis, Gliocidin causes death by lowering the level of guanine nucleotides inside the cell to upset the nucleotide balance. Essentially, Gliocidin is a prodrug, and as such it undergoes a metabolic process involving several key molecules before it finally works.

  When Gliocidin enters the cellular interior of a glioblastoma, it begins a special journey where it encounters its first key player, nicotinamide-phosphate ribosyltransferase (NAMPT), an enzyme that converts gliocidin into gliocidin mononucleotide, followed by a second enzyme- -Nicotinamide ribonucleotide adenylyltransferase 1 (NMNAT1) takes over the transformation task and further converts the gliocidin mononucleotide into GAD+, which is a specialised Gliocidin adenine dinucleotide.

  Perhaps you have heard of nicotinamide adenine dinucleotide (NAD+), which has a great reputation in cellular metabolism as a coenzyme involved in a wide range of biochemical reactions. But GAD+ came along to take some of the limelight away from NAD+, which can act as a NAD+ analogue to bind to the IMPDH2 enzyme and inhibit the enzyme's activity. Originally, the IMPDH2 enzyme is responsible for the production of guanine nucleotides, and with the perturbation of GAD+, the guanine nucleotide output drops dramatically. On the other hand, the production of adenine nucleotides was not affected, so that the purine nucleotide balance of the cell was disrupted, the ability to synthesise DNA was reduced, and the cell eventually died due to replication stress.

  In a mouse model of glioblastoma, the authors found that Gliocidin could penetrate the blood-brain barrier with the blood and subsequently progressively accumulate gradually in the peripheral tissues of the brain. In mice treated with Gliocidin, tumour progression was slowed, mouse survival was significantly improved, and Gliocidin was effective in the absence of T cells.

  In addition, some existing drugs can also help to take Gliocidin's efficacy to another level, such as the chemotherapy drug temozolomide, which can enhance the expression of NMNAT1, which is equivalent to adding a fire to the activation of Gliocidin. Mouse experiments have also shown that the combination of the two molecules can further prolong the survival time of tumour-bearing mice.

  In the future, Gliocidin will require further experiments to confirm its effects on the immune system, such as whether it suppresses the immune response,’ the review article states. After these issues are resolved, Gliocidin will hopefully become a highly promising new drug for glioblastoma, making it possible to attack this difficult to treat tumour.’