Study reveals targetable mechanism behind high-risk predisposition gene in pediatric medulloblastoma microbiologystudy

Discoveries announced today by St. Jude Children’s Research Hospital provide a scientific rationale for the targeted treatment of a type of pediatric medulloblastoma. Children who inherit a deficient ELP1 gene have an increased risk of developing SHH-medulloblastoma, a subtype of a malignant pediatric brain tumor.

The researchers showed how ELP1 deficiency leads cells to turn off a tumor suppressor protein, p53, allowing cancer development. The work further revealed how an MDM2-targeted therapy could turn the anticancer protein back on, thereby extending survival in model systems. The findings were published in Cancer Cell.

“We made the initial discovery of ELP1 deficiency predisposing children to SHH-medulloblastoma seven years ago, but now we’ve worked through its mechanism to an actual pharmacological intervention,” said senior co-corresponding author Paul Northcott, Ph.D., St. Jude Center of Excellence in Neuro-Oncology Sciences (CENOS) director and Department of Developmental Neurobiology member. “We started with a gene in a spreadsheet and now have identified a potential targeted treatment.”

In a prior study, Northcott’s lab found children who inherited a nonfunctional variant of ELP1 were much more likely than their peers to develop SHH-medulloblastoma, but the reason was unclear. Adding to the confusion, virtually every cell of the body expresses ELP1, but its variant only predisposed children to this specific brain cancer subtype. The scientists created mouse models without functional ELP1 to study why this occurs.

“We found that loss of ELP1 led to reduced activity of the tumor suppressor protein p53,” Northcott said. The protein p53 is among the most highly mutated in human cancers. It acts as a molecular brake on cell growth, suppressing tumors. Cancers, therefore, often leverage mutated p53 to keep growing unchecked.

In children, p53 loss is commonly associated with brain cancer from a specific cell type— granule neuron progenitors in the cerebellum. This cell type is the origin of SHH-medulloblastoma. As ELP1 loss reduces p53 activity, it also leads to SHH-medulloblastoma. That connection to p53 inspired the scientists to identify a potential way to reactivate its activity in these tumors.

Targeted therapy reawakens p53 in childhood brain cancer

“We showed pharmacologically restoring p53 activity using MDM2 inhibition is an exciting avenue toward a targeted therapy for SHH-medulloblastoma,” Northcott said.

MDM2 stops p53 activity by sparking the destruction of the tumor suppressor. When the researchers blocked MDM2, preventing its destruction, active p53 could kill cancerous cells. In mouse models of SHH-medulloblastoma that harbor ELP1 loss, MDM2 inhibition significantly increased survival length. The strategy is now being evaluated for its potential inclusion in clinical trials. It is particularly attractive as multiple MDM2 inhibitors are in active clinical trials.

“Our findings emphasize how fundamental research is critical to innovating better treatments for kids with cancer,” Northcott said. “This is a prime example, showing how lab research to resolve a biochemical mechanism can move us away from current treatments with undesirable long-term side effects and toward more effective and safe, targeted therapies, especially for pediatric brain tumors.”