Researchers have identified a new metabolic vulnerability responsible for driving cancer growth in a type of medulloblastoma, a form of pediatric brain cancer. Their discovery centers on the role of DHODH, an enzyme routinely used for normal metabolism. The team from McMaster University in Hamilton, Ontario learned that inhibiting DHODH in medulloblastoma of the MYC-amplified subtype stopped cancer growth but did not interfere with surrounding normal neural stem cells. Results of the study are published in Cancer Cell.
DHODH is involved in the synthesis of pyrimidine, one of the body’s key building blocks. In normal cells, if this pathway is blocked, they can rely on a salvage pathway to maintain pyrimidine synthesis. “But in medulloblastoma, those cells do not have a proper salvage pathway,” explains senior author Sheila Singh, PhD, of the division of neurosurgery at McMaster University. If the regular pathway is eliminated by inhibiting DHODH, then the medulloblastoma cell can’t make pyrimidine and die. “But the awesome thing is that normal neural stem cells, which are the non-cancerous counterpart of medulla blastoma cells, can use their salvage pathway and still make pyrimidine,” she adds. Normal neural stem cells are essential to children’s brains because they are still developing and populating their brains with cells.
“What we’ve discovered is a selective metabolic vulnerability that only exists in medulloblastoma and not in normal cells so if we use a drug to target DHODH in medulloblastoma, the normal neural stem cells will be spared,” Singh adds.
In their experiments, Singh and colleagues first used CRISPR screens of human medulloblastoma cells. They created a library of CRISPR guides that cut out every single gene in the genome, and then added that library to medulloblastoma cells to determine which genes are essential drivers of medulloblastoma or are functionally essential to the cells. They also performed a comparative screen on medulloblastoma cells and normal neural stem cells to see if they could identify any potential therapeutic window of genes or gene products that would be effective in cancer but don’t disturb the normal cells.
After identifying the pathway for pyrimidine biosynthesis—and DHODH especially—they next tested a variety of DHODH inhibitors on the cells. “We saw right away that it was killing all the medulloblastoma cells, not the normal cells,” said Singh.
Next, the researchers moved to a mouse model where human medulloblastoma cells donated from Singh’s pediatric patients were engrafted into mice. The team observed the same results. “Since we actually were testing it on human cells grown in a living animal model, hopefully this should translate into working in humans as well,” Singh added. The team identified a lead DHODH inhibitor, the small molecule BAY2402234, which is currently in advanced human trials for leukemia and other brain cancers, such as IDH-mutant glioma and diffuse intrinsic pontine glioma (DIPG).
It should be noted that of the four types of medulloblastoma, only one type of medulloblastoma, known as MYC-amplified, appears to have this DHODH vulnerability. MYC-amplified cancer, where MYC is a key driving oncogene, represents about 30% of medulloblastoma cases. It spreads easily and has the worst prognosis. By the time children are diagnosed, the cancer has often spread throughout the brain and into their spinal fluid.
“With MYC- amplified medulla blastoma, those children will undergo standard therapy – surgery, chemo, radiation – and then they relapse after that because their cells acquire these resistance mechanisms and we have no treatment options for them,” says Singh. The team also detected signs that this DHODH-associated pathway is also enriching at the relapse stage. “And so not only could we treat upfront the worst kind of measurable blastoma but maybe we can also try this on children who have relapsed and have no other treatment options,” she added. The researchers are also hopeful the approach might bypass the side effects of current treatments which can impair children’s brain development even if their cancer is successfully treated.
