DDRE-11. TARGETING FATTY ACID BIOSYNTHESIS IN GLIOBLASTOMA

Abstract

We recently provided evidence that endoplasmic reticulum (ER) stress promotes fatty acid (FA) biosynthesis in glioblastoma (GBM) cancer stem cells (GSCs). We determined that Stearoyl CoA Desaturase 1 (SCD), a key FA desaturase, is essential for regulating ER homeostasis in GSCs, and showed that these cells are highly susceptible to pharmacological perturbation of SCD activity. An impaired SCD activity leads to the toxic accumulation of saturated FA and activates cell death signaling mediated by the ER sensor Inositol-requiring enzyme 1 (IRE1). This in turn promotes an IRE1-mediated mRNA decay of key DNA damage repair genes and impairs the ability of GSCs to repair DNA damage caused by radiation or chemotherapy. Consequently, combining SCD inhibition with temozolomide (TMZ) leads to major cytotoxicity both in TMZ-sensitive, and TMZ-resistant patient-derived GBM cells. Pharmacological inhibition of SCD delivered through the nasal route in mice, had a remarkable therapeutic benefit in patient-derived orthotopic GSCs mouse models, yet the modest brain permeability of the currently available SCD inhibitors precludes their clinical translation. To overcome this challenge, we have recently acquired a first-in-class, clinically relevant SCD inhibitor. This compound has undergone extensive pharmacokinetic and pharmacodynamic studies which confirmed brain permeability, efficacy, and safety in small animals and non-human primates. We show that the combination of this SCD inhibitor with TMZ is effective both in cultured GSCs, and in preclinical GSCs orthotopic mouse models. Our results support the clinical investigation of this new class of SCD inhibitors, in combination with TMZ, in patients diagnosed with GBM.