TMET-02. THERAPEUTIC EFFICACY OF A NOVEL BRAIN PENETRANT SCD INHIBITOR ON BREAST CANCER BRAIN METASTASES

Abstract Brain metastases are a significant therapeutic challenge and associated with high morbidity mortality. Recent evidence suggests that brain have increased fatty acid synthesis compared to extracranial tumors. The enzyme stearoyl-CoA desaturase (SCD), which converts saturated long-chain acids into monounsaturated acids, is often upregulated in breast cancer metastasis (BCBM) considered promising target. However, the lack of penetrant SCD inhibitors limited their use patients. This study aimed investigate efficacy clinical-stage inhibitor treat BCBM. We found pharmacologic inhibition multiple cell lines induced cytotoxicity, mainly by apoptosis. Gas chromatography/mass spectrometry confirmed desaturation index, measures activity, was significantly lower after treatment. triggered endoplasmic reticulum (ER) stress DNA damage due higher production reactive oxygen species. Further, decreased repair inhibiting homology-directed vitro mouse model cancer. Notably, led decrease tumor growth subcutaneous increase overall survival BCBM model. Cytotoxicity enhanced when this combined either damage-inducing agent (temozolomide or radiation) PARP (Niraparib). Finally, we observed combination therapy Niraparib Our results suggest alone strategy