MEDB-87. Transcriptome-driven drug repurposing in group 3 medulloblastoma

Across the molecular spectrum of medulloblastoma (MB), group 3 (G3) tumors are the most aggressive with <50% five-year survival, the lowest of all MB subgroups. G3 MB tumors are characterized by frequent metastases at diagnosis, unique methylation profiles, MYC amplification, and i17q, but these unique molecular features have yet to be exploited for therapeutic purposes despite their contribution to the disease process. As such, we sought to address this gap in survivorship by identifying FDA-approved compounds with the potential to inhibit cellular processes critical to G3 MB tumor proliferation and metastasis, aiming to exploit the unique molecular pathogenesis of G3 tumors. Guided by analysis of RNA-sequencing data from locally obtained, patient-derived MB samples against the LINCS chemical perturbagens database, we identified nortriptyline (NT), a tricyclic antidepressant, as a candidate MB therapeutic due to: 1) its ability to revert the transcriptomic signature of G3 MB to a normal cerebellum-like state and 2) its ability to cross the blood-brain barrier. We first identified the IC(50 )of NT in D425 and HDMB03 cells as 28μM and 20μM, respectively. Then, we observed that NT increased apoptosis of HDMB03 cells 3-fold by flow cytometry and confirmed our observations with Western blotting of apoptotic markers. Additionally, NT treatment resulted in abrogation of colony formation, impairment of wound healing, and inhibition of cell migration and invasion in vitro in HDMB03 cells. In all, transcriptome-driven drug repurposing holds great promise, as identifying novel uses for compounds with a known safety profile can deliver effective treatments into the hands of both patients and physicians in an expedited manner when compared to traditional means.