A nicotinamide-mimetic prodrug shows promise against glioblastoma in mouse studies
BioNews Central | 11-22-2024
Glioblastoma is a highly aggressive and untreatable brain tumor that constitutes roughly half of all primary brain tumors. According to the National Brain Tumor Society, the five-year survival rate for this condition is merely 7 percent. This dismal statistic highlights the critical necessity for innovative therapies to combat this formidable disease.
In a study just published in Nature, a research team led by Memorial Sloan Kettering Cancer Center has made a promising discovery involving a compound named gliocidin. The research team conducted extensive studies using both genetically engineered mouse models of glioblastoma and human tumor samples that were grown in mouse brains. In these experiments, gliocidin demonstrated the ability to effectively target and kill cancer cells while sparing healthy cells, a crucial aspect in cancer treatment where minimizing damage to normal tissue is paramount.
The mechanism through which gliocidin operates is particularly intriguing. The compound is a nicotinamide-mimetic prodrug that transforms into its cancer-fighting form, gliocidin–adenine dinucleotide (GAD), through the action of the enzyme nicotinamide nucleotide adenylyltransferase 1 (NMNAT1). GAD interferes with the tumor’s ability to synthesize purines, which are essential for guanine production. Guanine is a nucleotide that tumor cells require for proliferation and survival. By disrupting this synthesis process, gliocidin creates an imbalance in nucleotide levels within the cancer cells, leading to cellular stress. This stress ultimately triggers a cascade of events that culminates in cell death, effectively reducing tumor growth.
The study led by postdoctoral fellow Yu-Jung Chen, PhD, under the supervision of Luis F. Parada, PhD, who serves as the Director of MSK’s Brain Tumor Center, revealed additional insights into the efficacy of gliocidin. The research found that when gliocidin was combined with the chemotherapy drug temozolomide, there was a notable enhancement in tumor cell death. This combination therapy not only increased the effectiveness of the treatment but also improved survival rates in laboratory models, offering a potential new avenue for therapeutic intervention.
Dr. Parada elaborated on the discovery process: “We identified gliocidin by screening a vast array of compounds for their ability to selectively target glioblastoma cells.” The ability of gliocidin to cross the blood-brain barrier is particularly noteworthy. The blood-brain barrier is a selective permeability barrier that protects the brain from harmful substances but also poses a significant challenge for delivering therapeutic agents. Gliocidin’s capacity to penetrate this barrier enables it to reach tumors directly and exert its effects, making it a promising candidate for further research and development.
In addition to its low toxicity observed in animal studies, gliocidin presents several advantages that could facilitate its progression through preclinical and clinical trials. The drug’s selective action on cancer cells minimizes adverse effects commonly associated with traditional chemotherapy, which often indiscriminately affects both malignant and healthy tissues. As a result, gliocidin may offer a more tolerable treatment option for patients battling glioblastoma.
The implications of this research extend beyond just glioblastoma treatment. Understanding how gliocidin interacts with cancer cells may provide valuable insights into similar aggressive tumors and lead to the development of alternative therapeutic strategies. As researchers continue to explore the full potential of this compound, they may uncover additional mechanisms that could be targeted in other forms of cancer, paving the way for more effective treatments.
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This article is based on materials provided by Memorial Sloan Kettering Cancer Center.
