(Boston) – High-risk neuroblastoma is an aggressive childhood cancer with poor treatment outcomes. Despite intensive chemotherapy and radiation therapy, less than 50 percent of these children survive for five years. While the genetics of human neuroblastoma have been widely studied, actionable therapies are limited.
Today, researchers from the Feng lab at Boston University School of Medicine (BUSM), working with scientists at the Simon lab at the Perelman School of Medicine at the University of Pennsylvania (Penn), have not only discovered why this cancer is so aggressive, but also reveal a promising therapeutic approach to treat these patients. These results appear online in the journal Research against cancer, a journal of the American Association for Cancer Research.
“Our work highlights targeted therapy to treat this at-risk group of patients, possibly leading to improved survival,” said corresponding author Hui Feng, MD, PhD, associate professor of pharmacology and medicine at BUSM .
The research, led by Nicole M. Anderson, PhD, former postdoctoral fellow at Feng Lab and currently a researcher at Simon Lab, combined analysis of patient samples with genetic analysis of a zebrafish model of high neuroblastoma. risk and cell culture gene knockdown studies to understand the contribution of Dihydrolipoamide S-Succinyltransferase (DLST), a metabolic enzyme, and found that it promotes the metastatic spread of this type of cancer.
“We show that high DLST expression predicts not only poor patient outcomes, but disease aggression in human neuroblastoma as well. In the zebrafish neuroblastoma model, even a modest increase in DLST protein levels can accelerate the onset of neuroblastoma, increase tumor burden and promote metastasis. ”says Celeste Simon, PhD, co-author and scientific director and researcher at the Abramson Family Cancer Research Institute, UPenn at Penn. Conversely, they found that a 50 percent reduction in DLST alters the initiation of neuroblastoma and suppresses tumor aggression. Depletion of DLST in human neuroblastoma cells decreases cell growth and induces apoptosis (cell death).
The researchers used cell lines with models of zebrafish and mouse neuroblastoma to test the therapeutic efficacy of IACS-010759, a drug in clinical trials for the treatment of other cancers. “Our studies revealed that human neuroblastoma cells are responsive to IACS treatment, which slowed tumor cell growth in all models tested,” said Feng.
She hopes this study will provide IACS-010759 as a targeted therapy for children with this aggressive disease.
Funding was provided by: NM Anderson: Alex’s Lemonade Stand Foundation, GR-000000165. J. Athoe and A. Lam: Boston University, Undergraduate Research Opportunity Scholarship. J. Athoe and A. Kennedy: Alex’s Lemonade Stand Foundation, Pediatric Oncology Student Education Award. AT Look at: NIH, R35CA210064. MC Simon: NIH, P01 CA104838 and R35 CA197602. H. Feng: NIH, CA134743 and CA215059; Boston University, 1UL1TR001430 and Ralph Edwards Career Development Chair; Leukemia Research Foundation, Young Investigator Award; the American Cancer Society, RSG-17-204-01-TBG; and St. Baldrick Foundation, Career Development Scholarship.
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