EXTH-23. PRECLINICAL EFFICACY OF A TARGETED, BRAIN PENETRANT INHIBITOR OF FATTY ACID DESATURATION IN GLIOBLASTOMA

Abstract

Abstract There is increasing evidence that targeting de novo fatty acid synthesis could be effective for the treatment of primary and metastatic brain tumors, but brain penetrant inhibitors of this pathway are still lacking. We have previously reported that Stearoyl CoA Desaturase (SCD), a desaturase enzyme which converts saturated fatty acids into their unsaturated counterparts is a therapeutic target in glioblastoma (GBM). We showed that SCD exerts a cytoprotective role by protecting GBM cells against lipotoxicity and is essential for maintaining self-renewal and tumor initiating properties in GBM stem cells (GSCs). Using a panel of patient derived GSCs, mouse orthotopic GSC models, isogenic astrocytes models of gliomagenesis as well as in silico analysis, we report that in addition to SCD1, a second SCD isoform is also essential for GSCs maintenance. Further we demonstrate that while EGFR/PI3K/AKT signaling promotes lipogenesis, the activation of RAS/MEK/ERK signaling creates a metabolic vulnerability and sensitizes to SCD inhibitors. We tested a first-in-class, clinically relevant SCD inhibitor and showed that this compound effectively inhibits fatty acid desaturation in GSCs in a mouse orthotopic GSC model. Importantly, using different GSCs mouse models, we demonstrate that this SCD inhibitor can effectively increase overall survival as a monotherapy. Further, SCD inhibition impairs DNA-damage repair via homologous recombination thereby sensitizing to the standard of care therapeutics for GBM, ionizing radiation and temozolomide (TMZ). Consequently, combining this inhibitor with TMZ in mouse orthotopic GSC models leads to a significantly increased overall survival. Altogether, our results provide a deeper understanding of de novo fatty acid dynamics in GBM and support the clinical testing of a new SCD inhibitor, with favorable pharmacokinetic and pharmacodynamic properties, in patients diagnosed with GBM.