Quantitative high-throughput phenotypic screening of pediatric cancer cell lines identifies multiple opportunities for drug repurposing.

Min Shen,Eugene N Muratov,Sherif Farag,Hongmao Sun,Ya-Qin Zhang,Stephen J Capuzzi,William P Janzen,Natalia J Martinez,Rosita Asawa,Julie Blatt,Ajit Jadhav,Elizabeth Cunningham,Alexander Tropsha,Anton Simeonov

doi:10.18632/oncotarget.23462

Abstract

Drug repurposing approaches have the potential advantage of facilitating rapid and cost-effective development of new therapies. Particularly, the repurposing of drugs with known safety profiles in children could bypass or streamline toxicity studies. We employed a phenotypic screening paradigm on a panel of well-characterized cell lines derived from pediatric solid tumors against a collection of ∼3,800 compounds spanning approved drugs and investigational agents. Specifically, we employed titration-based screening where compounds were tested at multiple concentrations for their effect on cell viability. Molecular and cellular target enrichment analysis indicated that numerous agents across different therapeutic categories and modes of action had an antiproliferative effect, notably antiparasitic/protozoal drugs with non-classic antineoplastic activity. Focusing on active compounds with dosing and safety information in children according to the Children's Pharmacy Collaborative database, we identified compounds with therapeutic potential through further validation using 3D tumor spheroid models. Moreover, we show that antiparasitic agents induce cell death via apoptosis induction. This study demonstrates that our screening platform enables the identification of chemical agents with cytotoxic activity in pediatric cancer cell lines of which many have known safety/toxicity profiles in children. These agents constitute attractive candidates for efficacy studies in pre-clinical models of pediatric solid tumors.

Highlights

Drug repurposing or repositioning, the use of drugs for indications other than what they were initially intended, has been offered as a strategy for drug development in oncology programs
To identify new therapeutic options for pediatric cancer, we screened the NIH Chemical Genomics Center (NCGC) Pharmaceutical Collection (NPC)[21] and Mechanism Interrogation Plate (MIPE) [18,19,20] small molecule collections of approved and investigational drugs using a 1,536-well format quantitative high-throughput screening (qHTS) assay against a panel of pediatric cancer cell lines
The panel consisted of 19 well-characterized cell lines derived from childhood solid tumors, namely Ewing’s sarcoma (EWS), central nervous system (CNS) tumors, neuroblastoma (NB), osteosarcoma (OS), and rhabdomyosarcoma (RMS) (Table 1 and Supplementary Table 1)

Summary

Introduction

The use of drugs for indications other than what they were initially intended, has been offered as a strategy for drug development in oncology programs This approach has special potential for childhood cancers and other rare or orphan diseases, where the expected return on new drug development has been a disincentive to pharmaceuticals [1, 2]. A third approach to repurposing, which exploits the polypharmacology of drugs to discover new drug indications, is the use of phenotypic screening [14,15,16,17] This approach interrogates drug candidates in pediatric cancer models in an unbiased fashion and has the advantage of providing information on large numbers of drugs in relatively short periods of time. Identifying approved drugs with previously unrecognized anticancer properties has the potential to reveal new mechanisms and biological processes involved in carcinogenesis or drug resistance

Methods

Results

Conclusion