TMET-36. ACID CERAMIDASE INHIBITION EXPLOITS SPHINGOLIPID VULNERABILITIES IN IDH MUTANT GLIOMAS

Abstract The presence of the IDH mutation in gliomas is a major classifier brain tumor subtypes and has several important implications for cancer growth. Our recent work uncovered that IDH-mutant tumors are susceptible to increased apoptosis via alterations sphingolipid pathway due their excess production pro-apoptotic ceramides over pro-proliferative sphingosine 1-phosphate (S1P). To end, we proposed this rheostat can be modulated induce cell death IDHmut by targeting acid ceramidase, critical enzyme gliomas. We hypothesize pharmacological inhibition ceramidase will increase ceramide levels therefore IDHmutgliomas. Using preliminary drug screen, have identified group haloacetate C2-ceramide derivatives known as SOBRACs potently inhibit ceramidase. selected five candidate compounds from family assessed effectiveness each 3 I (BT142, TS603, & U251mut) (GSC923, GSC827, U251wt) patient-derived glioma lines, well non-immortalized normal human astrocytes, using CCK8 viability assay. results indicate SOBRAC drugs nearly 10 times more potent compared lines. Additionally, effective than other inhibitors, making them attractive potential novel therapeutics. date, azide-SOBRAC most family, with EC50 value 300 nM BT142 cells (IDHmutmut