Leveraging a metabolic vulnerability to overcome chemoresistance in recurrent Ewing Sarcoma

Ewing sarcoma is a pediatric cancer that generally responds well to initial therapies. This is due to the high expression of SLFN11, a DNA damage response protein that confers a vulnerability to DNA-damaging therapeutics, such as chemotherapy. However, upon relapse, Ewing sarcoma often becomes SLFN11-deficient and consequently less responsive to chemotherapy.

In the search to overcome chemoresistance in relapsed Ewing sarcoma, St. Jude scientists analyzed a patient-derived Ewing sarcoma model. This model allowed them to examine what prompts therapeutic resistance when there is reduced SLFN11 expression. Through transcriptomic and metabolic profiling, the investigators identified enhanced glycerophospholipid (GPL) biosynthesis, a metabolic process that creates parts of the cell membrane. By targeting GPL biosynthesis, they were able to restore sensitivity to DNA-damaging agents, demonstrating the potential of the metabolic process as a future therapeutic target.

“This study underscores how metabolic vulnerabilities can be exploited to counter therapy resistance in Ewing sarcoma. Importantly, it highlights the promise of noninvasive metabolic imaging to track treatment-relevant biology and help guide therapy optimization,” said corresponding author Puneet Bagga, PhD, Department of Radiology. “Our goal is to translate these biomarkers into clinical research so we can better detect recurrence risk, improve trial stratification and ultimately reduce chemotherapy-related toxicity while improving outcomes for children.”

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