New Enzyme Targeting Strategy Holds Promise for Neuroblastoma Treatment

Neuroblastoma, a malignant tumor primarily affecting infants and young children, remains a leading cause of cancer-related mortality in this age group. Despite aggressive treatment modalities—including surgery, chemotherapy, and immunotherapy—the prognosis for patients with high-risk neuroblastoma is often grim, particularly when the disease metastasizes. Current standard therapies, such as retinoic acid differentiation therapy, have shown limited efficacy, with many patients experiencing treatment resistance and relapse.

Recent research conducted by a team from Karolinska Institutet and Lund University in Sweden offers a potentially revolutionary approach to treating this challenging cancer. The study, published in the *Proceedings of the National Academy of Sciences* on June 17, 2025, identifies two antioxidant enzymes, PRDX6 and GSTP1, as promising new targets for therapeutic intervention. According to Dr. Marie Arsenian Henriksson, a professor at the Department of Microbiology, Tumor and Cell Biology at Karolinska Institutet, "The children who survive often have lifelong cognitive difficulties due to the harsh treatment, so there is a great need for new forms of therapies for children with neuroblastoma."

The rationale for this innovative strategy lies in the high levels of oxidative stress associated with neuroblastoma cells, particularly those driven by the amplification of the MYCN oncogene. These cells often rely heavily on peroxiredoxins, including PRDX6, which help neutralize reactive oxygen species (ROS) that can induce cell death. The researchers found that high expression levels of PRDX6 contribute to tumor growth and resistance to standard therapies.

The study's findings indicate that dual inhibition of PRDX6 and GSTP1 can induce apoptosis (programmed cell death) in neuroblastoma cell lines while promoting differentiation into healthy neurons. The researchers utilized both genetic knockdown techniques and small-molecule inhibitors, including MJ33 for PRDX6 and EZ for GSTP1, to demonstrate that blocking these enzymes reduced MYCN expression and activated neuronal differentiation pathways that differ from those engaged by retinoic acid. Notably, this dual treatment resulted in increased lipid droplet accumulation and spontaneous neuronal firing, suggesting enhanced functional maturation.

The implications of this research are significant, as the dual-targeting approach not only showcases a distinct mechanism of action compared to traditional RA therapy but also hints at a broader reprogramming of the tumor's metabolic pathways. Proteomic analyses revealed minimal overlap between the protein expressions induced by PRDX6/GSTP1 inhibition and those from RA treatment, indicating that this strategy could provide an alternative route for neuroblastoma therapy.

In mouse xenograft models, the administration of these inhibitors led to a marked reduction in tumor burden, suppression of proliferation markers, and increased expression of neural proteins such as SCG2 and tubulin B3. Given that one of the inhibitors, EZ (ezatiostat hydrochloride), has received orphan drug designation from the U.S. Food and Drug Administration for myelodysplastic syndrome, there is potential for accelerated clinical trials aimed at pediatric neuroblastoma patients.

As researchers and clinicians continue to seek safer and more effective treatment options for neuroblastoma, the identification of PRDX6 and GSTP1 as therapeutic targets offers renewed hope for improved patient outcomes. This enzyme-targeting strategy not only aims to enhance the survival rates of affected children but also aspires to minimize the long-term cognitive and physical side effects associated with current treatment regimens. The future of neuroblastoma therapy may hinge on further exploration and validation of these novel approaches, as they represent a crucial step towards shifting the fate of cancer cells from malignancy to maturity.