French and US research teams have identified metabolic vulnerabilities in aggressive forms of medulloblastoma (MB), the most common malignant brain tumor in children. Studies have shown that fatty acids (FAs) accumulate within lipid droplets (LDs) in high-risk tumors, and that disrupting lipid storage weakens tumor cells and triggers widespread cell death. These findings suggest potential therapeutic strategies that could reduce the reliance on treatments associated with severe long-term toxicity while improving outcomes for children with poor prognoses.

Speaking with MediQuality, a Medscape Network platform, Pierluigi Calò, MD , a pediatric hematology-oncology specialist at Queen Fabiola Children’s University Hospital in Brussels, Belgium, provided clinical perspectives.

“Medulloblastoma is a common malignant brain tumor in children,” said Calò. “Among all pediatric brain tumors, it is the most common malignant cancer, although it remains rare overall. It is, however, highly aggressive and requires multimodal treatment, combining surgery, chemotherapy, and, depending on the child’s age, radiotherapy.”

Divergent Prognoses

Not all MBs have the same prognoses. “Over the past 10 years, our understanding of these tumors has advanced substantially,” Calò said. “Genetic analyses have identified four main groups of MB, along with multiple subgroups.”

These biological differences translate into wide variations in outcomes. “In favorable cases, 5-year survival exceeds 90%, whereas survival drops to around 50% at 5 years in the highest-risk cases,” Calò said. “Alterations involving TP53 and MYC are particularly concerning and are associated with a very poor prognosis. The current challenge is to reduce long-term treatment toxicity in children with favorable-risk disease while intensifying therapy for those whose survival is threatened.”

Multimodal Analysis

This challenge formed the rationale for the study led by researchers from the Institut Curie in collaboration with the Istituto Pasteur Italia — Fondazione Cenci Bolognetti, Sapienza University, Rome, Italy, and other international academic institutions, including the Baylor College of Medicine in Houston and the University of Pittsburgh, Pittsburgh. This study revealed a novel molecular mechanism for blocking the growth of MB, the most common malignant brain tumor in children.

To obtain a comprehensive view of disease biology, researchers analyzed 384 tumor samples from the international MB COMICS cohort, including patients from France, the US, Germany, and Canada. To date, this is the largest international cohort dedicated to pediatric MB. The results of this study, which identified “lipid droplets” as a critical and targetable vulnerability, have been published in Cancer Cell.

Using an integrative bioinformatics strategy, researchers have combined five layers of omics data — genomic, proteomic, phosphoproteomic, metabolomic, and clinical data — to characterize tumor cell biology. “This is a remarkable piece of work,” Calò said. “Its strength lies in the integration of established approaches such as proteomics and transcriptomics with newer techniques, particularly lipidomic, which focuses on lipid metabolism.”

He also emphasized the importance of international collaboration. “This study highlights the value of partnerships across borders, which we are also involved in, notably with KU Leuven and other European teams,” he said.

Lipid Vulnerability

The analysis revealed marked metabolic heterogeneity within group 3 MBs, including a distinctive lipid signature characterized by specific FA compositions in tumor cells. This feature was also observed in a subgroup defined by the activation of the MYC oncogene, which is associated with a particularly poor prognosis.

A detailed examination of the tumor samples revealed the rapid accumulation of FAs within LDs. These structures support tumor cell survival by protecting against oxidative stress and ferroptosis, a regulated form of cell death, while supplying mitochondria with energy that fuels tumor growth.

Protecting tumor cells may also be a key vulnerability. In preclinical models, the inhibition of diacylglycerol O-acyltransferase 1 (DGAT1), an enzyme essential for LD formation, triggers extensive tumor cell death. Combining DGAT1 inhibitors with conventional chemotherapy further enhances antitumor effects in preclinical settings, leading to greater tumor cell destruction.

Clinical Implications

Does this discovery open the door to new treatment strategies for children with high-risk diseases? “It is still too early to be overly optimistic,” Calò cautioned. “The findings need to be validated in nonmurine models. The authors also acknowledge that DGAT1 inhibitors have limited ability to cross the blood-brain barrier, which remains a major challenge in MB.”

However, he underscored the broader implications. “If confirmed, this work identifies a tumor-specific biologic dependency,” Calò said. “By demonstrating that group 3 MBs rely on a specific lipid metabolic pathway, it becomes possible to envision more targeted approaches. Such strategies could reduce reliance on chemotherapy and radiotherapy, whose toxic effects are especially damaging to the developing brain.”

This story was translated from MediQuality.