Grants and Contracts per year
Grants and Contracts Details
Hypothesis: 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 this interaction alter the metabolic phenotype of ES tumors to support proliferation. 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. Specific aims: This proposal focuses on the centralized theme that aberrant glycogen is part of the malignant transformation of ES tumors. We will first investigate how ES-glycogen affects cellular metabolism through regulation of AMPK (Aim 1). Then, we will explore whether targeting ES-glycogen metabolism is an effective therapeutic option both as a single agent and in combination with AMPK activating agents (Aim 2). The unique team of investigators with expertise in cancer biology and metabolomics, glycogen architecture, and translational and clinical treatment of ES patients, are perfectly suited to tackle the hypothesis and research plan. Defining the molecular events connecting ES-glycogen and AMPK would provide a strong scientific rationale for the future evaluation of metformin as an anti-ES agent.
|Effective start/end date||12/21/18 → 5/1/20|
Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.
- 1 Finished
Institutional Research Grant
1/1/17 → 12/31/19
Project: Research project