Preclinical efficacy of ribavirin in SHH and group 3 medulloblastoma.

Abstract

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.

• Authors: Sakibul Huq, Nivedha V Kannapadi, Joshua Casaos, Tarik Lott, Raphael Felder, Riccardo Serra, Noah L Gorelick, Miguel A Ruiz-Cardozo, Andy S Ding, Arba Cecia, Ravi Medikonda, Jeff Ehresman, Henry Brem, Nicolas Skuli, Betty M Tyler
• Journal: Journal of neurosurgery. Pediatrics (J Neurosurg Pediatr) Vol. 27 Issue 4 Pg. 482-488 (Feb 05 2021) ISSN: 1933-0715 [Electronic] United States
• PMID: 33545678 (Publication Type: Journal Article)

Chemical References

• EIF4E protein, human
• Eukaryotic Initiation Factor-4E
• Hedgehog Proteins
• SHH protein, human
• Ribavirin
• EZH2 protein, human
• Enhancer of Zeste Homolog 2 Protein

Topics

• Animals
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Cerebellar Neoplasms (genetics, metabolism, pathology)
• Enhancer of Zeste Homolog 2 Protein (drug effects, metabolism)
• Eukaryotic Initiation Factor-4E (drug effects, metabolism)
• Hedgehog Proteins (genetics)
• Humans
• Medulloblastoma (genetics, metabolism, pathology)
• Mice
• Ribavirin (pharmacology)
• Xenograft Model Antitumor Assays