OBJECTIVE Medulloblastoma, the most common pediatric brain malignancy, has Sonic Hedgehog (SHH) and group
3 (Myc driven) subtypes that are associated with the activity of eukaryotic initiation factor 4E (eIF4E), a critical mediator
of translation, and enhancer of zeste homolog 2 (EZH2), a histone methyltransferase and master regulator of transcription.
Recent drug repurposing efforts in multiple solid and hematologic malignancies have demonstrated that eIF4E and
EZH2 are both pharmacologically inhibited by the FDA-approved antiviral drug ribavirin. Given the molecular overlap
between medulloblastoma biology and known ribavirin activity, the authors investigated the preclinical efficacy of repurposing
ribavirin as a targeted therapeutic in cell and animal models of medulloblastoma.
METHODS Multiple in vitro assays were performed using human ONS-76 (a primitive SHH model) and D425 (an aggressive
group 3 model) cells. The impacts of ribavirin on cellular growth, death, migration, and invasion were quantified
using proliferation and Cell Counting Kit-8 (CCK-8) assays, flow cytometry with annexin V (AnnV) staining, scratch
wound assays, and Matrigel invasion chambers, respectively. Survival following daily ribavirin treatment (100 mg/kg) was
assessed in vivo in immunodeficient mice intracranially implanted with D425 cells.
RESULTS Compared to controls, ribavirin treatment led to a significant reduction in medulloblastoma cell growth
(ONS-76 proliferation assay, p = 0.0001; D425 CCK-8 assay, p < 0.0001) and a significant increase in cell death (flow
cytometry for AnnV, ONS-76, p = 0.0010; D425, p = 0.0284). In ONS-76 cells, compared to controls, ribavirin significantly
decreased cell migration and invasion (Matrigel invasion chamber assay, p = 0.0012). In vivo, ribavirin significantly
extended survival in an aggressive group 3 medulloblastoma mouse model compared to vehicle-treated controls (p =
CONCLUSIONS The authors demonstrate that ribavirin, a clinically used drug known to inhibit eIF4E and EZH2, has
significant antitumor effects in multiple preclinical models of medulloblastoma, including an aggressive group 3 animal
model. Ribavirin may represent a promising targeted therapeutic in medulloblastoma.