A University of Michigan-led study has revealed a previously unknown vulnerability in Group-3 medulloblastoma, an aggressive and incurable form of this childhood brain cancer. The research, published in Cancer Cell, identifies the metabolic enzyme dihydrolipoyl transacetylase (DLAT) as a key player in a newly discovered form of cell death dubbed cuproptosis. The findings suggest a promising therapeutic avenue that could be exploited using an existing drug, elesclomol, to improve outcomes for patients with these tumors.
“Although copper is important for brain development, we know that too much of it or too little of it can cause diseases,” said senior author Sriram Venneti, MD, PhD, a professor of pathology and pediatrics and a member of Rogel Cancer Center at University of Michigan. “Cuproptosis is a newly discovered form of copper-dependent cell death. Even though we don’t know how it works, there is growing evidence that some types of cancers are sensitive to it.”
Medulloblastomas are categorized into four subgroups—WNT, SHH, Group-3, and Group-4. Group-3 medulloblastoma is the most aggressive of the four subgroups and patients diagnosed with it have the worst prognoses. Group-3 medulloblastoma tumors are typically characterized by amplification or overexpression of the MYC oncogene. Despite improvements in diagnosis and patient stratification, this subgroup of medulloblastomas remains resistant to treatment with high rates of metastasis.
“More work needs to be done to understand the biology of these tumors for therapeutic development,” the researchers wrote.
To identify new targets for therapy, the team took a multi-omic approach using transcriptomic, epigenomic, and metabolomic profiling of patient-derived samples, cell lines, and animal models. Data analyses revealed that DLAT, the E2 subunit of the pyruvate dehydrogenase complex, was upregulated in a subset of Group-3 medulloblastomas and associated with poor patient survival.
“MYC-driven group-3 medulloblastomas (MBs) are malignant pediatric brain cancers without cures,” the researchers wrote. “To define actionable metabolic dependencies, we identify upregulation of dihydrolipoyl transacetylase (DLAT), the E2-subunit of pyruvate dehydrogenase complex (PDC) in a subset of group-3 MB with poor prognosis.”
DLAT was found to be induced by the MYC protein, which is itself regulated by the metabolic enzyme isocitrate dehydrogenase 1 (IDH1). Suppression of IDH1 reduced MYC and downstream DLAT expression, suggesting this regulatory pathway is central to how these tumors alter their metabolism for survival and growth and represents a new therapeutic target.
The researchers demonstrated that DLAT not only plays a role in energy production and redox balance but also sensitizes tumor cells to cuproptosis when exposed to elevated copper levels. The research team determined that the copper ionophore elesclomol, which increases intracellular copper levels, could potentially affect this regulatory pathway to slow the development of Group-3 medulloblastoma tumors. The team found that it effectively killed tumor cells with high DLAT expression and mouse models treated with elesclomol showed reduced tumor burden and increased survival.
“Finding a drug that can penetrate into the brain is usually a huge challenge,” Venneti said. “Elesclomol can cross the blood-brain barrier and enter into the brain even when it’s present in very small concentrations.”
Elesclomol has been previously tested in adults with solid tumors, increasing the possibility of repurposing it for pediatric brain cancers. “Tumors are heterogenous, and it’s possible that elesclomol is better suited for patients who have brain tumors with higher levels of c-MYC and DLAT,” Venneti said. “We hope to start clinical trials soon and see if our findings can help us fight this type of cancer.”
This research builds on earlier studies that have shown the role of MYC amplification in the aggressiveness and treatment resistance of Group-3 medulloblastomas. The new study adds to those findings by revealing a metabolic vulnerability linked to DLAT and copper metabolism and demonstrates a new mechanistic explanation for why certain tumors may be more susceptible to cuproptosis.
Next steps for the University of Michigan research team include developing a more detailed understanding the molecular mechanisms of cuproptosis, determining whether DLAT or MYC expression can serve as biomarkers for treatment selection, and eventually launching clinical testing of elesclomol in pediatric patients.
