Targeting SCD triggers lipotoxicity of cancer cells and enhances anti-tumor immunity in breast cancer brain metastasis mouse models.

Breast cancer brain metastases (BCBM) are a significant cause of mortality and are incurable. Thus, identifying BCBM targets that reduce morbidity and mortality is critical. BCBM upregulate Stearoyl-CoA Desaturase (SCD), an enzyme that catalyzes the synthesis of monounsaturated fatty acids, suggesting a potential metabolic vulnerability of BCBM.

Targeting de novo lipid synthesis induces lipotoxicity and impairs DNA damage repair in glioblastoma mouse models.

Deregulated de novo lipid synthesis (DNLS) is a potential druggable vulnerability in glioblastoma (GBM), a highly lethal and incurable cancer. Yet the molecular mechanisms that determine susceptibility to DNLS-targeted therapies remain unknown, and the lack of brain-penetrant inhibitors of DNLS has prevented their clinical evaluation as GBM therapeutics. Here, we report that YTX-7739, a clinical-stage inhibitor of stearoyl CoA desaturase (SCD), triggers lipotoxicity in patient-derived GBM stem-like cells (GSCs) and inhibits fatty acid desaturation in GSCs orthotopically implanted in mice.

Orthotopic brain tumor models derived from glioblastoma stem-like cells.

There is an urgency for identifying effective therapies for glioblastoma (GBM), an incurable and lethal primary malignant brain tumor. Patient-derived xenograft mouse models, in which glioma stem cells, which retain the characteristics of the original tumor, are implanted into the brain of immunocompromised mice, represent a well-suited model for studying GBM. Such models are essential for studies involving the tumor microenvironment and for testing experimental therapeutics for brain tumors.

Intranasal delivery of experimental compounds in orthotopic brain tumor mouse models.

Effective therapeutics for malignant primary brain tumors, such as glioblastomas (GBMs), are urgently needed. To facilitate and expedite early-phase GBM therapeutic development, we describe a protocol that allows the intranasal delivery of experimental compounds in GBM orthotopic mouse models. Compounds delivered through this route can bypass the blood-brain barrier and thus help validate effective therapeutic targets for GBMs.