Preclinical efficacy of ribavirin in SHH and group 3 medulloblastoma

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  • Hunterian Neurosurgical Research Laboratory, Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
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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.

ABBREVIATIONS AnnV = annexin V; CCK-8 = Cell Counting Kit-8; eIF4E = eukaryotic initiation factor 4E; EZH2 = enhancer of zeste homolog 2; SHH = Sonic Hedgehog.

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Contributor Notes

Correspondence Betty M. Tyler: Johns Hopkins University School of Medicine, Baltimore, MD. btyler@jhmi.edu.

INCLUDE WHEN CITING Published online February 5, 2021; DOI: 10.3171/2020.8.PEDS20561.

N.S. and B.M.T. contributed equally to this work.

Disclosures Dr. Brem reports receiving research funding that includes grants from NIH, Johns Hopkins University, Arbor Pharmaceuticals, Bristol-Myers Squibb, AcuityBio Corp.,* and philanthropy and being a consultant for AsclepiX Therapeutics, StemGen, InSightec, Accelerating Combination Therapies,* Camden Partners,* LikeMinds, Inc.,* Galen Robotics, Inc.,* NexImmune, and Nurami Medical.* Ms. Tyler reports being a patent holder of Accelerating Combination Therapies.* (*Includes equity or options.)

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