New enzyme target for neuroblastoma

Scientists have identified a possible new treatment for neuroblastoma in children.

Dr Ninib Baryawno, at the Karolinska Institutet, Sweden, and colleagues looked at the potential of the enzyme dihydroorotate dehydrogenase as a potential target for treatment.

This enzyme was highlighted in genome sequencing of more than 700 solid tumour cell lines from patients. It is an essential enzyme in synthesis of pyrimidine, found in the nucleic acids DNA and RNA.

The inhibition of DHODH is already being investigated as a therapy for patients with haematologic cancers.

In the new work on neuroblastoma, high DHODH expression appeared to be a risk factor for aggressive disease, worse overall and worse event-free survival.

The scientists, writing in *JCI Insight*, state: "A subset of tumours with the highest DHODH expression was associated with a dismal prognosis, with a five-year survival of less than 10%."

But in tests on mice, treatment with a DHODH inhibitor called brequinar, led to dramatically reduced tumour growth and extended survival.

A combination of brequinar and the chemotherapy drug temozolomide cured the majority of neuroblastomas in mice, "indicating a highly active clinical combination therapy", they report.

"Overall, DHODH inhibition combined with temozolomide has therapeutic potential in neuroblastoma and we propose this combination for clinical testing," they conclude.

Dr Baryawno said: “Through targeted treatment with specific DHODH blockers, we show in different cell and animal studies that cancer cells die, and that tumours stop growing.

“This is very promising, as DHODH blockers have been shown to be well-tolerated in clinical trials for other disorders.”

Olsen, T. K. et al. DHODH is an independent prognostic marker and potent therapeutic target in neuroblastoma. *JCI Insight* 9 August 2022; doi: 10.1172/jci.insight.153836

[abstract]

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