BMET-34DRUG REPURPOSING DISCOVERS BETA-SITOSTEROL AS AN EFFECTIVE THERAPEUTIC AGENT AGAINST MELANOMA BRAIN METASTASES IN VIVO

Despite major therapeutic advances in the management of patients with metastatic melanoma, brain metastases remain an intractable problem. It has proven difficult to identify and target single genes or pathways critical to brain metastasis formation. Here, we explore a more global and preventive treatment approach to melanoma brain metastases within an established xenograft model of human melanoma. Mice were injected intracardially and followed for six weeks with whole-body BLI and brain MRI. Tumor-bearing brains, adrenals, ovaries, and femurs were harvested and enzymatically dissociated before three tumor cell samples from each organ were flow-sorted and subjected to RNA sequencing. We were able to define a 108-gene brain metastasis gene signature, and queried the Connectivity Map database for candidate drugs, i.e. drugs that induce an opposite gene expression profile in various cancer cell lines. We found the cholesterol analogue beta-sitosterol to effectively inhibit brain metastases and improve survival, both in established and preventive therapeutic settings. Beta-sitosterol extensively suppressed the MAPK pathway, and effectively reduced mitochondrial respiration through Complex I inhibition. This novel mechanistic synergy may open new avenues of systemic therapy against metastatic melanoma, as increased mitochondrial respiration is a key mediator of resistance to MAPK-targeted drugs.