Fellowship for Lyndsay Young: Aberrant Glycogen Modulates Metabolism in Ewing's Sarcoma

Ewing’s sarcoma (ES) is the second most common pediatric bone malignancy affecting ~10,000 children, adolescents, and young adults worldwide each year (1). Approximately half of all patients with Ewing sarcoma will develop either recurrent or metastatic disease, with less than 20% of such patients surviving long-term. The standard of care for ES patients includes multi-agent chemotherapy to treat documented or potential metastatic disease, coupled with surgery and/or irradiation to treat the primary tumor. Although some incremental advances have been made in the last three decades through intensification of conventional chemotherapy agents, more significant improvements will likely depend on the identification of novel treatment strategies. Two hallmark clinical features of ES are: 1) the accumulation of intracellular glycogen deposits that are Periodic acid-Schiff positive (PAS+) during pathological analysis and 2) the EWS-FLI1 fusion oncogene. Contribution of EWS-FLI1 to tumorigenesis and epigenetics is well defined (2–7), but little is known about the biology and pathology of ES glycogen accumulation nor has ES glycogen metabolism been explored as an anti-ES target. The aims presented in this pre-doctoral phase of the proposal are designed to interrogate ES glycogen metabolism in promoting tumorigenesis. My strong preliminary data demonstrate ES-glycogen has aberrant architecture with long chains, increased branching pattern and high phosphate content resembling polyglucosan bodies (PGBs). Further, these ES-PGBs control the activity of AMP-activated protein kinase (AMPK) via tight binding thus impacting cellular metabolism and growth. Excitingly, I have demonstrated that targeting ES-PGBS using a glycogen synthase inhibitor reduces in vivo tumor growth. I will expand on these findings in Aim 1 by characterizing the relationship of ES-PGBs and AMPK via high-throughput metabolomics profiling and innovative biochemical assays. Additionally, I will expand on my interrogation of ES-PGBs as a therapeutic intervention. In Aim 2, I plan to extend my pre-doctoral training in cellular metabolism of a rare cancer to my postdoctoral training in the emerging field of metabolic phenotyping and personalized medicine. I intend to bridge the gap between high-throughput cancer metabolic profiling and personalized medicine.