Aberrant Glycogen is a Metabolic Vulnerability of Ewing's Sarcoma

  • Sun, Ramon (PI)

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Ewing Sarcoma (ES) is the second most common pediatric bone cancer in adolescent and young adults. Intensified chemotherapy regimens have incrementally improved recurrent or metastatic ES outcomes, motivating research and development of new treatment options to combat this deadly disease. A hallmark of ES is the accumulation of large glycogen granules, clinically known as Periodic acid-Schiff (PAS) positive. The origin and pathology of ES-glycogen have not been defined nor pursued as therapeutic targets. We recently discovered that the ES-glycogen is both hyper-phosphorylated and hyper-branched making it architecturally distinct from normal glycogen. We present strong evidence showing that ES-glycogen is critical for ES proliferation. Our data establish that ES-glycogen results from loss of malin, an E3 ubiquitin ligase that regulates glycogen architecture. We demonstrate that ES-glycogen binds to AMP-activated protein kinase (AMPK) with high affinity and renders AMPK inactive. Further, we show that a genetic manipulation normalizing ES-glycogen architecture significantly reduces glucose flux and delays xenograft ES tumor growth by 70%. Finally, using a small molecule inhibitor targeting glycogen synthase (GYS) that reduces ES-glycogen accumulation, we reduced xenograft tumor growth. Based on these results, we hypothesize that ES-glycogen drives cellular proliferation by modulating cellular metabolism, and it is a promising therapeutic target. The overall objective of this study is to interrogate the origin and molecular pathology of ES-glycogen, define its role as a modulator of metabolism through direct-interaction with AMPK and finally, to validate targeting ES-glycogen as an effective therapeutic option.
Effective start/end date8/1/197/31/22


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