STEM-02. THERAPEUTIC INTERVENTION OF LUNG-, BREAST-, AND MELANOMA-BRAIN METASTASIS

Abstract

Abstract BACKGROUND The incidence of brain metastases (BM) is tenfold higher than that of primary brain tumours. BM predominantly originate from primary lung, breast, and melanoma tumours with a 90% mortality rate within one year of diagnosis, posing a large unmet clinical need to identify novel therapies against BM.This unmet clinical need is largely attributed to a small population of cancer stem cells (CSCs), termed BM-initiating cells (BMICs), that are able to escape a primary tumour, drive metastasis and facilitate the formation of a secondary tumour in the brain. METHODS Using a large in-house biobank of patient-derived BMIC lines, the Singh Lab has generated murine orthotopic patient-derived xenograft models of BM and captured a “premetastatic” population of BMICs that have just seeded the brains of mice before forming clinically detectable tumours: a cell population that is impossible to detect in human patients but represents a therapeutic window wherein metastasizing cells can be targeted and eradicated before establishing clinically detectable tumours. RESULTS RNA sequencing of pre-metastatic BMICs from all three primary tumour models with subsequent Connectivity Map analysis identified a lead compound that exhibits selective anti-BM activity in vitro. Preliminary in vivo work has shown that this lead compound reduces the tumor burden of treated mice compared to vehicle control while providing a significant survival advantage. Ongoing mechanistic investigations aim to delineate the protein target of this compound in the context of the observed selective anti-BMIC phenotype. CONCLUSION Identification of novel small molecules that target premetastatic BM cells could prevent the formation of BM and dramatically improve the prognosis of at-risk cancer patients.