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In search of druggable targets for GBM amino acid metabolism

Eduard H. Panosyan, MD, LA BioMed at Harbor-UCLA Medical Center; Henry J. Lin, MD, LA BioMed at Harbor-UCLA Medical Center; Joseph L. Lasky III, MD, LA BioMed at Harbor-UCLA Medical Center


Amino acid (AA) pathways may contain druggable targets for GBM. We reviewed GBM databases to screen for such targets (http://r2.amc.nl) using expression levels of ~100 genes for AA related enzymes. One-third of the genes were differentially expressed between 3 GBM and 5 “normal” brain datasets or were associated with survival (supplemented with analysis of TCGA in 22 AA KEGG pathways). Protein expression for these enzymes was also analyzed (proteinatlas.org) in high grade gliomas. We detected differences in glutamate and urea cycle related enzymes, including expression of BCAT1 and ASL being high, and ASS1 low in GBM. Proneural and neural groups (TCGA subtypes) had low expression of all 3. High expression of all 3 correlated with worse outcome. ASL and ASS1 protein levels were mostly undetected in high grade gliomas, whereas BCAT1 was high. ASPA and GOT1 (AST) had lower expression in GBM (associated with poor outcomes). The neural group had higher AST and ASPA, but lower GPT (ALT). Differences were also noted with GAD1 and GAD2 (which convert glutamate to GABA). These enzymes were lower in GBM, but ABAT was not (catabolizes GABA). Lower levels of both GAD2 and ABAT showed a trend for poor PFS. All 3 GABA related genes were lower in mesenchymal tumors, which in contrast showed higher IDO1 and TDO2. GSS was not differentially expressed, but higher levels were linked to poor PFS. PRODH, a putative tumor suppressor, was lower in GBM. Higher levels predicted poor survival. Other genes also had differential expression in GBM, correlating with outcomes. Thus, there may be potential targets that vary in TCGA subtypes, based on heterogeneity of AA metabolism.

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