High-throughput screening identifies candidate drugs for the treatment of recurrent respiratory papillomatosis

Faris Alkhilaiwi; Siddartha Paul; Dan Zhou; Xiaohu Zhang; Feibai Wang; Nancy Palechor-Ceron; Kelli Wilson; Rajarshi Guha; Marc Ferrer; Nazaneen Grant; Craig Thomas; Richard Schlegel; Hang Yuan

doi:10.1016/j.pvr.2019.100181

High-throughput screening identifies candidate drugs for the treatment of recurrent respiratory papillomatosis

Papillomavirus Res. 2019 Dec:8:100181. doi: 10.1016/j.pvr.2019.100181. Epub 2019 Aug 22.

Authors

Affiliations

¹ Department of Pathology, Georgetown University, Medical School, Washington DC, 20057, USA; Department of Oncology, Georgetown University, Medical School, Washington DC, 20057, USA; Department of Biochemistry and Molecular Biology, Georgetown University, Medical School, Washington DC, 20057, USA; College of Pharmacy, King Abdul Aziz University, Jeddah, Saudi Arabia.
² Department of Pathology, Georgetown University, Medical School, Washington DC, 20057, USA.
³ Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, USA.
⁴ Department of Otolaryngology, Georgetown University, Medical School, Washington DC, 20057, USA.
⁵ Department of Pathology, Georgetown University, Medical School, Washington DC, 20057, USA. Electronic address: Hang.Yuan@georgetown.edu.

Abstract

Recurrent respiratory papillomatosis (RRP) is a benign neoplasm of the larynx caused mainly by human papillomavirus type 6 or 11 and its standard treatment involves repeated surgical debulking of the laryngeal tumors. However, significant morbidity and occasional mortality due to multiple recurrences occur. Conditional reprogramming (CR) was used to establish a HPV-6 positive culture from an RRP patient, named GUMC-403. High-throughput screening was performed at the National Center for Advanced Technology (NCATS) to identify potential drugs to treat this rare but morbid disease. GUMC-403 cells were screened against the NPC library of >2800 approved drugs and the MIPE library of >1900 investigational drugs to identify new uses for FDA-approved drugs or drugs that have undergone significant research and development. From the two libraries, we identified a total of 13 drugs that induced significant cytotoxicity in RRP cells at IC50 values that were clinically achievable. We validated the efficacy of the drugs in vitro using CR 2D and 3D models and further refined our list of drugs to panobinostat, dinaciclib and forskolin as potential therapies for RRP patients.

Keywords: Dinaciclib; Drug sensitivity; Forskolin; High-throughput screening; Panobinostat; Primary cell culture; Recurrent respiratory papillomatosis; Repurposing.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Biopsy
Cell Culture Techniques
Cell Line
Cell Survival / drug effects
Disease Models, Animal
Disease Susceptibility
Dose-Response Relationship, Drug
Drug Discovery* / methods
High-Throughput Screening Assays* / methods
Human papillomavirus 6 / physiology
Humans
Mice
Microbial Sensitivity Tests
Papillomavirus Infections / complications
Papillomavirus Infections / drug therapy*
Papillomavirus Infections / etiology
Papillomavirus Infections / virology
Respiratory Tract Infections / drug therapy*
Respiratory Tract Infections / etiology

Supplementary concepts

Recurrent respiratory papillomatosis