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New combination therapy shows potential to improve survival in children with neuroblastoma
Children who suffer a relapse of the aggressive cancer known as neuroblastoma have a slim chance of survival. A group that included researchers at the Karolinska Institutet in Sweden has now shown that DHODH blockers, which are well tolerated in humans, can cure neuroblastoma in mice when given in combination with chemotherapy. The study, published in the journal JCI Insight, paves the way for clinical trials of this combination therapy. Neuroblastomas are tumors of nerve tissue that are typically diagnosed in very young children, usually before the age of two. The disease affects around 15 to 20 children in Sweden every year and...
New combination therapy shows potential to improve survival in children with neuroblastoma
Children who suffer a relapse of the aggressive cancer known as neuroblastoma have a slim chance of survival. A group that included researchers at the Karolinska Institutet in Sweden has now shown that DHODH blockers, which are well tolerated in humans, can cure neuroblastoma in mice when given in combination with chemotherapy. The study, published in the journal JCI Insight, paves the way for clinical trials of this combination therapy.
Neuroblastomas are tumors of nerve tissue that are typically diagnosed in very young children, usually before the age of two. The disease affects around 15 to 20 children in Sweden each year and is the deadliest form of cancer in infants. This new study shows that the protein DHODH (dihydroorotate dehydrogenase), involved in metabolism and DNA synthesis, also plays a key role in promoting tumor growth of aggressive neuroblastomas.
Through targeted treatment with specific DHODH blockers, we show in various cell and animal studies that cancer cells die and tumors stop growing. This is very promising as DHODH blockers have been shown to be well tolerated in clinical trials for other diseases.”
Ninib Baryawno, senior researcher at the Department of Women and Children's Health, Karolinska Institutet, and one of the corresponding authors of the study
Potential to improve survival
When researchers combined DHODH blockers with chemotherapy already used to treat children with neuroblastoma, they managed to cure mice with an aggressive variant of the disease.
“This combination therapy should be tested clinically because it has the potential to improve survival in children with neuroblastoma,” says Baryawno. “This is urgently needed as the chances of survival in the event of a relapse are unfortunately low with current treatments.”
The study was carried out in close collaboration with researchers at Massachusetts General Hospital and the Harvard Stem Cell Institute in the USA. David Sykes, a senior author in Boston, commented:
"This is an exciting result with real potential to help patients. It also highlights the importance of international collaboration."
By analyzing patient data from over 600 children with neuroblastoma, researchers found that tumors with high levels of DHODH are more aggressive and deadly. They then treated cell cultures and mice with a specific DHODH blocker called Brequinar.
Weakens the “engine” of the tumor
When the researchers analyzed gene expression in the tumors, they found that brequinar reduced the activity of the MYCN gene, one of the “engines” that drive tumor growth. However, after treatment, the tumors began to grow again. This led the researchers to combine Brequinar with chemotherapy, which turned out to be a successful recipe and cured the sick mice.
“Neuroblastoma is a disease that begins very early in development, even in the fetal stage,” says joint first author Thale Kristin Olsen, a researcher at the Karolinska Institutet’s Department of Women’s and Children’s Health and the Department of Immunology, Genetics and Pathology. Uppsala University. “The next step in our research is to find out why the DHODH protein is so crucial for tumor growth.”
The study was funded by the Swedish Childhood Cancer Foundation, the Swedish Research Council, the Swedish Cancer Society, the Cancer Research Funds of Radiumhemmet and the Wenner-Gren Foundations. One of the corresponding authors, David B. Sykes, is a co-founder and shareholder of Clear Creek Bio, an advisor and shareholder of SAFI Biosolutions, and an advisor to Keros Therapeutics. No other conflicts of interest were reported.
Source:
Reference:
Olsen, TK, et al. (2022) DHODH is an independent prognostic marker and an effective therapeutic target in neuroblastoma. JCI Insight. doi.org/10.1172/jci.insight.153836.
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