Cancers, Vol. 12, Pages 3335: A Comparative Oncology Drug Discovery Pipeline to Identify and Validate New Treatments for Osteosarcoma
Cancers doi: 10.3390/cancers12113335
Authors: Jason A. Somarelli Gabrielle Rupprecht Erdem Altunel Etienne M. Flamant Sneha Rao Dharshan Sivaraj Alexander L. Lazarides Sarah M. Hoskinson Maya U. Sheth Serene Cheng So Young Kim Kathryn E. Ware Anika Agarwal Mark M. Cullen Laura E. Selmic Jeffrey I. Everitt Shannon J. McCall Cindy Eward William C. Eward David S. Hsu
Background: Osteosarcoma is a rare but aggressive bone cancer that occurs primarily in children. Like other rare cancers, treatment advances for osteosarcoma have stagnated, with little improvement in survival for the past several decades. Developing new treatments has been hampered by extensive genomic heterogeneity and limited access to patient samples to study the biology of this complex disease. Methods: To overcome these barriers, we combined the power of comparative oncology with patient-derived models of cancer and high-throughput chemical screens in a cross-species drug discovery pipeline. Results: Coupling in vitro high-throughput drug screens on low-passage and established cell lines with in vivo validation in patient-derived xenografts we identify the proteasome and CRM1 nuclear export pathways as therapeutic sensitivities in osteosarcoma, with dual inhibition of these pathways inducing synergistic cytotoxicity. Conclusions: These collective efforts provide an experime ntal framework and set of new tools for osteosarcoma and other rare cancers to identify and study new therapeutic vulnerabilities.
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