Unexpected discovery points to a possible route for childhood brain tumor treatments

When researchers at Lund University investigated how the molecule UM171 works, a molecule used to make blood stem cells multiply, they made an unexpected connection. The results provide new insights into how one of the most common malignant brain tumors in children could be treated in the future. 

UM171 is a synthetic molecule developed by researchers at Université de Montréal. In stem cell research, it is used to increase the number of blood stem cells outside the body. The molecule helps cells retain their stem cell properties rather than mature into blood cells and stimulates their multiplication. The aim is to produce enough stem cells for transplantation in patients with serious blood diseases. In recent years, researchers, including those at Lund University, have shown that the molecule works by exploiting a protein called KBTBD4. This causes an important protein structure in the cell, called CoREST, to break down.

The same structure in the cell is also affected by mutations in the KBTBD4 gene, genetic changes that occur in a subgroup of aggressive brain tumors in children. Although the causes differ, the result is the same - the structure breaks down."

Agatheeswaran Subramaniam, researcher, Lund University

Medulloblastoma is the most common malignant brain tumor in children and affects around 15–20 children in Sweden each year. The tumor belongs to the group of embryonal brain tumors, which are thought to arise when immature cells in the developing brain do not mature as they should but continue to divide. Some cases of medulloblastoma are linked to mutations in KBTBD4. These tumors are very difficult to recreate in the laboratory because they arise early during brain development.

"It is striking that a small molecule and genetic mutations lead to the same effect in the cell. But while the molecule has a temporary effect, the mutations instead lead to a long-term shortage of CoREST, meaning that the cells remain in a stem cell-like state. This may contribute to the development of embryonal tumors," says Rohit Sivaprasad, doctoral student at Lund University.

The researchers also carried out a large-scale drug screen and found that HDAC inhibitors counteract the effects of KBTBD4 mutations. HDAC inhibitors are a type of drug that affects gene activity in cells. The study is an example of so-called drug repurposing, where an already approved drug is given a new use in another disease area. The findings provide new knowledge about how these brain tumors arise and point to a possible route towards future treatments.

"What is fascinating about research is that sometimes you find a fundamental mechanism that can help answer several different clinical questions. This study was carried out in the laboratory using blood stem cells. The next step is to test whether these drugs work in medulloblastoma tumors," concludes Agatheeswaran Subramaniam.