Abstract Details

Title Metabolomic and Lipidomic Profiling Reveals Distinct Subtypes of IDH-wildtype Glioblastoma and Shared Metabolic Features with IDH-mutant Astrocytoma Grade Four

Topic Neuro-oncology

Presentation(s) S28 - Neuro-oncology: Clinical and Practice Updates (5:06 PM-5:18 PM)

Poster/Presentation
Number 009

Objective To develop a biological understanding of glioma metabolism.

Background Glioblastoma is a metabolically diverse and aggressive brain tumor. We used untargeted metabolomics and lipidomics with supervised analysis to define metabolic changes within IDH-wildtype glioblastoma and IDH-mutant astrocytoma, grade 4, as well as to identify potential subclusters of metabolically distinct tumor types.

Design/Methods Brain tissue from IDH-wildtype glioblastoma (n = 38), IDH-mutant astrocytoma, Grade 4 (n = 5), and non-neoplastic controls (n = 20) underwent untargeted metabolomic and lipidomic profiling. Partial Least Squares Discriminant Analysis was followed by k-means clustering. ANOVA was used to identify significantly altered metabolites, with significance defined as fold change (FC) of greater than 2 and p-value correction based on a false discovery rate of 0.05. Heatmaps visualized differences, and pathway enrichment was performed using MetaboAnalyst 6.0.

Results Glioblastoma exhibited numerous significantly altered metabolites and lipids compared to controls, including increases in hypotaurine (FC 5.5, p = 9x10^-5) and sorbitol (FC 3.9, p = 0.003), and decreases in ribonic acid (FC -3.3, p = 1.6x10^-13) and arabitol (FC -2.9, p = 4.1x10^-20). K-means clustering revealed three distinct metabolic subtypes within IDH-wildtype glioblastoma. Cluster 1 showed increased galactose (p=0.02) and sucrose metabolism (p=0.009). Cluster 2 was characterized by increased glutathione metabolism (p=0.002). Cluster 3 demonstrated increased arginine biosynthesis (p=7.5x10^-4). IDH-mutant tumors exhibited 130-fold elevated levels of 2-hydroxyglutarate (2HG). Lipidomic profiling demonstrated numerous altered lipids in both tumor types compared to controls, including increases in sphingomyelin 40:1 (FC 157, p=4.4x10^-5) and decreases in phosphatidylcholine 39:7 (FC -2.8, p=3.0x10^-19) , but overall similar lipidomic profiles between the two tumor types.

Conclusions Metabolomic profiling identified three distinct subtypes of IDH-wildtype glioblastoma with unique metabolic signatures and revealed shared metabolic features between glioblastoma and IDH-mutant astrocytoma grade 4. Results highlight the potential for metabolomics to improve understanding of tumor biology and guide personalized treatment strategies for patients.

Authors/Disclosures
John Paul Aboubechara, MD, PhD (UC Davis Health Department of Neurology) PRESENTER	Dr. Aboubechara has nothing to disclose.
Yin A. Liu, MD, FAAN (UC Davis)	Dr. Liu has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Myrobalan. Dr. Liu has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Argenx.
Oliver Fiehn (UC Davis)	Oliver Fiehn has nothing to disclose.
Lina Dahabiyeh, PhD	Prof. Dahabiyeh has nothing to disclose.
Ruben Fragoso (UC Davis)	Ruben Fragoso has nothing to disclose.
Jonathan Riess	Jonathan Riess has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sanofi. Jonathan Riess has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Regeneron. Jonathan Riess has received personal compensation in the range of $500-$4,999 for serving as a Consultant for BMS. Jonathan Riess has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Janssen. Jonathan Riess has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Daiichi Sankyo. Jonathan Riess has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Amgen. Jonathan Riess has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche/Genentech. Jonathan Riess has received personal compensation in the range of $500-$4,999 for serving as a Consultant for SeaGen. Jonathan Riess has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck. Jonathan Riess has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier.
Rawad Hodeify (American University of Ras Al Khaimah)	Rawad Hodeify has nothing to disclose.
Orin Bloch (University of California Davis)	Orin Bloch has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Monteris Medical. Orin Bloch has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for BrainLab. The institution of Orin Bloch has received research support from NIH.
Vansh M. Patel, MBBS	Mr. Patel has nothing to disclose.
Orwa Aboud, MD, PhD (University of California Davis)	Dr. Aboud has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Aboud LLC.

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