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

// Min Shen 1, * , Rosita Asawa 1, * , Ya-Qin Zhang 1 , Elizabeth Cunningham 1 , Hongmao Sun 1 , Alexander Tropsha 3 , William P. Janzen 5 , Eugene N. Muratov 4 , Stephen J. Capuzzi 4 , Sherif Farag 4 , Ajit Jadhav 1 , Julie Blatt 2, 3 , Anton Simeonov 1 and Natalia J. Martinez 1 1 National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA 2 Division of Pediatric Hematology Oncology, University of North Carolina, Chapel Hill, NC, USA 3 Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA 4 Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA 5 Epizyme, Inc., Cambridge, MA, USA * Joint first authors Correspondence to: Natalia J. Martinez, email: natalia.martinez@nih.gov Keywords: drug repurposing; quantitative high-throughput screening; pediatric cancer; 3D cultures Received: August 10, 2017      Accepted: November 26, 2017      Published: December 19, 2017 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.