In the Netherlands, about three children a year develop an atypical teratoid rhabdoid tumor (ATRT). An ATRT usually occurs in the brain. Currently, a small proportion of these children are cured by surgery, intensive chemotherapy and high-dose radiation. Therefore, to increase the chances of cure, research into better treatments is of great importance.
Tumor cell death
Dr. Dennis Metselaar, postdoctoral researcher in the Hulleman group, and his colleagues investigated the effect of the drug gemcitabine on ATRT cells in the laboratory. They did so after testing more than 140 drugs on various forms of childhood brain tumors. This showed that ATRT, unlike the other brain tumor variants, is very sensitive to gemcitabine. The sonic hedgehog (SHH) variant was the most sensitive to the drug. This is the form that occurs in most children and is the most aggressive.
The researchers developed new models to conduct this study: mouse models and tumor cell cultures. They used tumor cells from a child treated for ATRT in the past. Large-scale tests with tumor cell cultures showed that gemcitabine was most effective for ATRT. They then validated the drug's effect on whole tumors in mice. This showed that after treatment, the mice lived more than 30% longer on average, even compared to existing therapy. In fact, two treated animals remained alive for the entire study period.
Metselaar: 'The research is in an early phase, but these results are hopeful. This is the first time we have seen mice in ATRT live significantly longer due to a single drug with minimal side effects.'
The results of this study were shared with the scientific community today in Cell Reports Medicine. The Hulleman group also made the new research models, tumor cell cultures and mouse models accessible to other researchers. The research was funded by KiKa.
Molecular level
To explain the precise action of the drug, Metselaar and his colleagues examined ATRT cells at the molecular level. 'We saw that gemcitabine reduces the SIRT1 protein in the cell. As a result, two other proteins increase: NF-kB and p53. Unlike many other (brain) tumors, these proteins are almost never mutated in ATRT, only suppressed. They then cause the tumor cells to die. Because of the direct link with SIRT1, and the specific influence of gemcitabine on this protein, we think this drug works so well.'
Next steps
The laboratory study shows that ATRT is highly sensitive to treatment with gemcitabine. Dr. Esther Hulleman, research group leader and principal investigator: 'These results show that this drug could possibly become part of the treatment of ATRT in combination with other drugs. The translation into a clinical trial is the next step. Because gemcitabine is already approved for the treatment of cancer in children, this should be accelerated. Then it will also become clear whether what we see in the lab actually causes more children with this form of cancer to be cured.'