Enzyme inhibitor strategy converts neuroblastoma cells into healthy neurons in mice

Researchers at Karolinska Institutet and Lund University in Sweden have identified a new treatment strategy for neuroblastoma, an aggressive form of childhood cancer. By combining two antioxidant enzyme inhibitors, they have converted cancer cells in mice into healthy nerve cells.

The study, “Combined targeting of PRDX6 and GSTP1 as a potential differentiation strategy for neuroblastoma treatment,” is published in the journal Proceedings of the National Academy of Sciences.

Neuroblastoma is a type of childhood cancer that affects the nervous system and is the leading cause of cancer-related death in young children. Some patients have a good prognosis, but those with metastatic tumors often cannot be cured despite modern combinations of surgery, radiation, chemotherapy and immunotherapy.

“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,” says Marie Arsenian Henriksson, professor at the Department of Microbiology, Tumor and Cell Biology at Karolinska Institutet.

Transform cancer cells

Differentiation therapy is a treatment method used in neuroblastoma that aims to transform cancer cells into more mature and healthy cells. The problem with the current retinoic acid differentiation therapy is that many patients do not respond to treatment, and about half develop resistance.

In collaboration with researchers at Lund University, Henriksson’s research team has shown that inhibition of two specific enzymes, PRDX6 and GSTP1, could be an alternative to retinoic acid treatment.

Neuroblastoma is characterized by high oxidative stress due to the active metabolism in the cancer cells. Tumors are therefore dependent on antioxidant enzymes such as PRDX6 and GSTP1 to manage the stress and avoid cell death. High levels of these enzymes are associated with a poorer prognosis.

“When we inhibit these enzymes in cell cultures as well as in mouse models, some of the tumor cells die while others mature into active, healthy neurons, impairing tumor growth,” says Judit Liaño-Pons, researcher at the Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet.

In the next step, the treatment will need to be tested in a clinical trial to investigate its safety and efficacy in children. One of the inhibitors has received orphan drug designation from the US Food and Drug Administration for the treatment of a different diagnosis in adults, making it a particularly promising drug candidate, according to the scientists.