Medulloblastoma is a relatively treatable pediatric brain cancer, with survival rates of about 80% if it's treated before it spreads. But in addition to surgery, most cases require chemotherapy and radiation—treatments that can harm brain development and set the stage for complications later in life.
Now, it appears that blocking a key enzyme could offer a better path to treating medulloblastoma. In a study published Nov 10. in Cancer Cell, scientists at McMaster University in Ontario described how they used a Bayer compound to curtail the cancer's spread in mouse models of its most aggressive subtype.
“This potential treatment pathway will allow us to kill the weeds but save the flower of the developing brain,” William Gwynne, first author, said in a press release.
The enzyme at the heart of the study is dihydroorotate dehydrogenase, or DHODH. It’s a key part of the de novo pyrimidine synthesis pathway, a pathway that ultimately leads to the creation of DNA and RNA and is known to be hijacked by cancers in their effort to grow. DHODH inhibitors like Sanofi’s Arava and Aubagio are FDA approved for the treatment of rheumatoid arthritis and multiple sclerosis, respectively, while others are under investigation against a wide breadth of conditions, including viruses and several types of cancer.
The McMaster team’s findings add one more potential indication to the list. The scientists homed in on DHODH by screening the genomes and metabolic processes of MYC-amplified medulloblastoma, a particularly deadly subtype of the brain cancer. They found alterations in the de novo pyrimidine synthesis pathway, and genetic analyses in cells and mice showed that knocking out DHODH could hinder medulloblastoma growth.
The scientists then sought to find out whether an orally administered DHODH inhibitor could stop tumor growth in mice. They treated mouse models of MYC-amplified medulloblastoma with a compound called BAY2402234, which, until this past January was under investigation by Bayer for the treatment of acute myeloid leukemia and glioma. The researchers found that the compound was able to reduce tumor growth and improve survival times in the mice, increasing their life spans from about 28 days in controls to around 38 days in the ones that were treated with BAY2402234.
While the team didn’t assess whether the compound had an impact on the brain development of young mice, they did find that it wasn’t harmful to cultured neural stem cells. In contrast, radiation is well known to impact neural stem cells in both children and adults and is thought to be the reason for brain damage associated with its use. Chemotherapy has been shown to kill brain cells as well, a possible explanation for the phenomenom of “chemo brain” described by patients.
Given these results and the fact that BAY2402234 has already been proven safe in humans during clinical trials at the equivalent doses to the ones used in their study, the researchers called for further optimizing DHODH inhibitors preclinically in medulloblastoma both alone and in combination with other treatments. If they perform well, the drugs should be translated to clinical research, the researchers wrote in their paper.