STEM-02. THERAPEUTIC INTERVENTION OF LUNG-, BREAST-, AND MELANOMA-BRAIN METASTASIS. (12th November 2021)

• Record Type: Journal Article
• Authors: Kieliszek, Agata; Bassey-Archibong, Blessing; Venugopal, Chitra; Singh, Sheila K
• Is Part Of: Neuro-oncology. Volume 23: Supplement 6(2021)
• Page Start: vi21
• Page End: vi21
• Publication Date: 2021-11-12
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noab196.078
• Languages: English
• ISSNs: 1522-8517

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.