High-risk neuroblastoma is an aggressive childhood cancer with poor treatment outcomes, and less than 50% of children survive for five years. A new study by researchers in the Feng lab at Boston University School of Medicine (BUSM), in collaboration with scientists in the Simon lab at the Perelman School of Medicine at the University of Pennsylvania (Penn), reveals why high-risk neuroblastoma is so aggressive and a potential therapeutic approach to treat patients.

Their findings are published in the journal Cancer Research, in a paper titled, “Metabolic Enzyme DLST Promotes Tumor Aggression and Reveals a Vulnerability to OXPHOS Inhibition in High-Risk Neuroblastoma.”

“High-risk neuroblastoma remains therapeutically challenging to treat, and the mechanisms promoting disease aggression are poorly understood,” wrote the researchers. “Here we show that elevated expression of dihydrolipoamide S-succinyltransferase (DLST) predicts poor treatment outcome and aggressive disease in neuroblastoma patients. DLST is an E2 component of the a-ketoglutarate (a-KG) dehydrogenase complex, which governs the entry of glutamine into the tricarboxylic acid cycle (TCA) for oxidative decarboxylation.

“Our work pinpoints a targeted therapy for treating this group of at-risk patients, likely leading to improved survival,” said corresponding author Hui Feng, MD, PhD, associate professor of pharmacology and medicine at BUSM.

The research was led by Nicole M. Anderson, PhD, a former postdoc in the Feng lab and a current fellow in the Simon lab. By combining patient sample analysis with genetic analysis of a zebrafish model of high-risk neuroblastoma, the researchers found that the metabolic enzyme, DLST, promoted metastatic spread of neuroblastoma.

“We show that elevated DLST expression not only predicts poor patient outcomes, but also disease aggression in human neuroblastoma. In the zebrafish model of neuroblastoma even a modest increase in DLST protein levels can accelerate neuroblastoma onset, increase tumor burden, and promote metastasis,” explained Celeste Simon, PhD, co-corresponding author and scientific director and investigator at the Abramson Family Cancer Research Institute, University of Pennsylvania.

They also observed that a 50% reduction in DLST impairs neuroblastoma initiation and suppresses tumor aggression. DLST depletion in human neuroblastoma cells decreases cell growth and induces apoptosis.

The researchers then utilized cell lines with zebrafish and mouse neuroblastoma models to test the therapeutic efficacy of IACS-010759, a drug that is in clinical trials for treating other cancers. “Our studies revealed that human neuroblastoma cells are sensitive to IACS treatment, which slowed tumor cell growth in all models tested,” said Feng.

“Together, these results demonstrate that DLST promotes neuroblastoma aggression and unveils OXPHOS as an essential contributor to high-risk neuroblastoma,” concluded the researchers.

Their findings pave a way for further studies targeting DLST and may lead to improve outcomes for patients with neuroblastoma.

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