(P 129) HIJACKED FUEL: GLYCOGEN-DRIVEN METABOLIC SHIFTS IN IDH1-MUTANT CHONDROSARCOMA

Objective: Conventional chondrosarcomas (CSA) remain therapeutically challenging. IDH1 mutations are common in CSA, but their metabolic consequences are not fully understood. This study investigates how alterations in glycogen metabolism and glycan biosynthesis relate to tumor grade, IDH status, metastasis, and survival.

Methods: We retrospectively reviewed 53 patients with primary CSA of bone (grades 2, 3, and dedifferentiated) diagnosed and treated at the University of Florida (2017–2024). Thirty-one cases with next-generation sequencing (NGS) data were analyzed using spatial metabolomics. Unstained slides from representative tumor blocks underwent MALDI mass spectrometry imaging. Glycogen and glycan levels were quantified and correlated with IDH1/2 status and clinical outcomes, including metastasis and survival.

Results: Distinct metabolic profiles emerged by tumor grade and IDH mutation status. Glycogen levels were highest in grade 3 and lowest in dedifferentiated CSA. Notably, IDH1-mutant tumors—unlike IDH2-mutant or wild-type tumors—exhibited elevated glycan levels despite reduced glycogen reserves, suggesting active glycogen utilization for glycan biosynthesis. The most striking metabolic divergence occurred between IDH1-mutant and wild-type tumors, driven by glycan enrichment in the former. Clinically, higher glycogen levels were associated with non-metastatic disease and survival, whereas lower glycogen and higher glycan levels were observed in patients with metastases or poor outcomes. These findings support a model in which glycogen is consumed to generate glycans that may promote dedifferentiation and progression in IDH1-mutant CSA.

Conclusion: IDH1-mutant CSA demonstrates a distinct metabolic phenotype marked by glycogen depletion and glycan accumulation. This reprogramming correlates with higher tumor grade, metastasis, and decreased survival. Spatial metabolomics may offer prognostic biomarkers and reveal metabolic vulnerabilities. This work lays the groundwork for future studies aimed at identifying targetable pathways within the glycogen-to-glycan axis, potentially opening new avenues for therapeutic intervention in CSA.