Abstract C082: SCD1 is a potent therapeutic target in MYC-amplified group 3 medulloblastoma
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AbstractMedulloblastoma (MB) is the most common pediatric brain tumor comprising of four subgroups: WNT, SHH, Group 3 (Gp3) and Group 4 (G4). Improved Standard of care has led to a greatly improved patient survival. However, 30% of patients still succumb to the disease and survivors are plagued with lifelong neuro-cognitive and neuro-developmental disorders. MYC amplified G3MB is a highly aggressive subgroup with a high frequency of metastasis and recurrence, leading to a bleak prognosis. Molecular understanding of G3MB is lacking and improved treatment options are urgently needed. Recent studies suggest a role for reprogrammed lipid metabolism, especially at recurrence. Here, we utilized comparative profiling of the G3MB and neural stem cells (NSC) lipidome with liquid chromatography-mass spectrometry (LC-MS). We identified a class of lipids whose differential abundance in G3MB renders these tumor cells sensitive to chemical inhibition of their biosynthesis. Pharmacological and genetic inhibition of the rate limiting enzyme of the de novo lipid synthesis pathway, Stearoyl-CoA Desaturase-1 (SCD1), completely abolishes self-renewal and proliferation in vitro, while supplementing cell culturing media with Oleic Acid (OA) fully restores these effects. Genetic knockout of SCD1 in G3MB cells significantly prolongs survival and reduced tumor burden in vivo. Moreover, administration of CAY10566, a SCD1 specific small molecule inhibitor significantly prolongs survival in vivo as well. RNA-seq, lipidomic and metabolomic analyses of G3MB treated with CAY10566 or DMSO is being employed to unravel SCD1-mediated mechanisms. Together, these data suggest that enzymes regulating lipid metabolism in G3MB represent potential targets for therapeutic translation.Citation Format: Stefan Custers, Laura Escudero, Yujin Suk, Dillon McKenna, William Gwynne, Iqra Chaudhry, Jeremy Chan, Andrew Quaile, Jason Moffat, Chitra Venugopal, Rafael Montenegro-Burke, Sheila Singh. SCD1 is a potent therapeutic target in MYC-amplified group 3 medulloblastoma [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C082.
