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

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

doi:10.1016/j.pvr.2019.100181

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.

Highlights

Recurrent respiratory papillomatosis (RRP) is a rare disease with an actual incidence of approximately 20,000 cases in the United States [1]
RRP is characterized by the growth of tumors in the respiratory tract caused by the human papillomavirus type 6 or 11 (HPV-6 or -11) and generally classified into two subtypes: juvenile-onset RRP (JORRP) and adult-onset RRP (AORRP) [2,3]
Computed Tomographic (CT) scanning revealed that there were multiple pulmonary nodules that had accelerated in growth

Summary

Introduction

Recurrent respiratory papillomatosis (RRP) is a rare disease with an actual incidence of approximately 20,000 cases in the United States [1]. RRP is characterized by the growth of tumors in the respiratory tract caused by the human papillomavirus type 6 or 11 (HPV-6 or -11) and generally classified into two subtypes: juvenile-onset RRP (JORRP) and adult-onset RRP (AORRP) [2,3]. JORRP cases, which develop before the age of 14, are more recurrent and aggressive than their AORRP counterpart [4]. Despite the fact that RRP primarily occurs on and around the laryngeal vocal cords, these growths can spread downward and affect the bronchi, the trachea and intermittently the lung parenchyma [2,3]. When progression to the lung occurs there are limited treatment options, the disease is fatal [5]

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Results

Conclusion