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Preclinical efficacy of ribavirin in SHH and group 3 medulloblastoma

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 =

0.0004).

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.

(DOI: 10.3171/2020.8.PEDS20561)

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