Repurposing the FDA-Approved Antiviral Drug Ribavirin as Targeted Therapy for Nasopharyngeal Carcinoma.

Sakibul Huq ,Andy S Ding ,Mariana Brait ,Michael Peters ,Ian Suk ,Tianna Zhao ,Riccardo Serra ,Nicolas Skuli ,Yuanxuan Xia ,David Sidransky ,Wataru Ishida ,Henry Brem ,Joshua Casaos ,Chenchen Ji ,Alexander Perdomo‐Pantoja ,Noah Gorelick ,Jeff Ehresman ,Jayanidhi Kedda ,Arba Cecia ,Manuel Morales ,Betty Tyler

doi:10.1158/1535-7163.mct-19-0572

Sakibul Huq , Andy S Ding + Show 19 more

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https://doi.org/10.1158/1535-7163.mct-19-0572

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Nasopharyngeal carcinoma (NPC) is a squamous cell carcinoma with a proclivity for systemic dissemination, leading many patients to present with advanced stage disease and fail available treatments. There is a notable lack of targeted therapies for NPC, despite working knowledge of multiple proteins with integral roles in NPC cancer biology. These proteins include EZH2, Snail, eIF4E, and IMPDH, which are all overexpressed in NPC and correlated with poor prognosis. These proteins are known to be modulated by ribavirin, an FDA-approved hepatitis C antiviral that has recently been repurposed as a promising therapeutic in several solid and hematologic malignancies. Here, we investigated the potential of ribavirin as a targeted anticancer agent in five human NPC cell lines. Using cellular growth assays, flow cytometry, BrdU cell proliferation assays, scratch wound assays, and invasion assays, we show in vitro that ribavirin decreases NPC cellular proliferation, migration, and invasion and promotes cell-cycle arrest and cell death. Modulation of EZH2, Snail, eIF4E, IMPDH, mTOR, and cyclin D1 were observed in Western blots and enzymatic activity assays in response to ribavirin treatment. As monotherapy, ribavirin reduced flank tumor growth in multiple NPC xenograft models in vivo Most importantly, we demonstrate that ribavirin enhanced the effects of radiotherapy, a central component of NPC treatment, both in vitro and in vivo Our work suggests that NPC responds to ribavirin-mediated EZH2, Snail, eIF4E, IMPDH, and mTOR changes and positions ribavirin for clinical evaluation as a potential addition to our NPC treatment armamentarium.

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Nasopharyngeal carcinoma (NPC) is a malignant squamous cell carcinoma most frequently seen in the pharyngeal recess whose hallmark is strong association with the Epstein-Barr Virus (EBV; ref. 1)
There is a notable lack of targeted therapies for NPC, despite working knowledge of multiple proteins with central roles in NPC cancer biology and significant prognostic value
We tested the effects of ribavirin on viability and proliferative properties of NPC in five different cell lines, including C666-1, the only available cell line natively positive for EBV

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Nasopharyngeal carcinoma (NPC) is a malignant squamous cell carcinoma most frequently seen in the pharyngeal recess whose hallmark is strong association with the Epstein-Barr Virus (EBV; ref. 1). NPC is endemic to southern China and has elevated incidence worldwide in northern Africa, the Inuits of Alaska, and Chinese immigrants in North America and Asia [2, 3]. The standard of care for NPC is radiotherapy for local disease and combination chemoradiotherapy for advanced or metastatic disease [1, 4]. Key therapies include antimetabolite and platinum-based therapies such as gemcitabine, cisplatin, and fluorouracil [1, 4, 5]. These approaches can achieve favorable local control for early-stage disease; NPC has a propensity for systemic dissemination, leading many patients to.

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