|Credit: National Cancer Institute|
Children who relapse into the aggressive neuroblastoma cancer form have little chance of survival. Researchers at Karolinska Institutet, among others, have been able to show that DHODH inhibitors, which have been well tolerated by humans, can cure neuroblastoma in mice if given together with cell toxins. The study has been published in the journal JCI Insight and paves the way for clinical trials of combination therapy.
Neuroblastoma is a tumor of nerve tissue that is diagnosed early, usually before the age of two. The disease affects about 15 to 20 children annually in Sweden and is the deadliest form of cancer in young children. The new study shows that the protein DHODH (dihydroorotate dehydrogenase), which is involved in metabolism and DNA synthesis, also has a key role in aggressive neuroblastoma and increases tumor growth.
Potential to improve survival
|Ninib Baryawno. |
Credit: Martin Stenmark
Through goal-controlled treatment with specific DHODH inhibitors, we show in various cell and animal studies that the cancer cells die and that the tumors stop growing. It is very promising because DHODH inhibitors have already been well tolerated in clinical trials for other disease states, say Ninib Baryawno, senior researcher at Department of Women's and Children's Health, Karolinska Institutet, and one of the study's correspondent authors.
When the researchers combined DHODH inhibitors with a cell toxin already used in the treatment of children with neuroblastoma, they managed to cure mice with an aggressive variant of the disease.
This combination therapy should be tested clinically as it has the potential to improve the survival of children with neuroblastoma. It is really long-awaited because the chances of surviving relapse are unfortunately small with today's treatments, says Ninib Baryawno.
The study was conducted in close collaboration with researchers at Massachusetts General Hospital and Harvard Stem Cell Institute in the United States. The researchers analyzed patient data from over 600 children with neuroblastoma and saw that tumors with high DHODH levels are more aggressive and fatal. They then treated cell cultures and mice with brequinar, which is a specific DHODH inhibitor.
Makes the cancer's "engine" weaker
|Thale Kristin Olsen. |
Credit: private collection
When the researchers analyzed the gene expression in the tumors, they saw that brequinar reduces the activity of the MYCN gene, one of the tumor's "engines" that drives growth. However, after treatment was completed, the tumors began to grow again. Therefore, the researchers tested combining brequinar with cell toxins, which proved to be a recipe for success that cured the diseased mice.
Neuroblastoma is a disease that begins already in fetal life. The next step in our research is to find out why the DHODH protein is so critical to tumor growth and its role during fetal development, say Thale Kristin Olsen, researcher at the Department of Women's and Children's Health, Karolinska Institutet and at the Department of Immunology, Genetics and Pathology, Uppsala University, which is one of the study's first authors.
The research was funded by the Children's Cancer Foundation, the Swedish Research Council, the Cancer Foundation, the Radium Home Research Funds and the Wenner-Gren Foundations. One of the corresponding authors, David B. Sykes, co-founder and owner of shares in Clear Creek Bio, is a consultant for and owns shares in SAFI Biosolutions and is a consultant for Keros Therapeutics. No other conflicts of interest have been reported.
Source/Credit: Karolinska Institutet | Felicia Lindberg