Quantitative high-throughput phenotypic screening of pediatric cancer cell lines identifies multiple opportunities for drug repurposing
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Min Shen1,*, Rosita Asawa1,*, Ya-Qin Zhang1, Elizabeth Cunningham1, Hongmao Sun1, Alexander Tropsha3, William P. Janzen5, Eugene N. Muratov4, Stephen J. Capuzzi4, Sherif Farag4, Ajit Jadhav1, Julie Blatt2,3, Anton Simeonov1 and Natalia J. Martinez1
1National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA
2Division of Pediatric Hematology Oncology, University of North Carolina, Chapel Hill, NC, USA
3Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA
4Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA
5Epizyme, Inc., Cambridge, MA, USA
*Joint first authors
Natalia J. Martinez, email: [email protected]
Keywords: drug repurposing; quantitative high-throughput screening; pediatric cancer; 3D cultures
Received: August 10, 2017 Accepted: November 26, 2017 Published: December 19, 2017
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.
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