A cross-species drug discovery pipeline to identify and validate new treatments for osteosarcoma

Abstract Purpose 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 extensiv...

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Published inbioRxiv
Main Authors Somarelli, Jason A, Rupprecht, Gabrielle, Erdem Altunel, Flamant, Etienne M, Rao, Sneha, Dharshan Sivaraj, Lazarides, Alexander L, Hoskinson, Sarah M, Sheth, Maya U, Cheng, Serene, So Young Kim, Ware, Kathryn E, Agarwal, Anika, Cullen, Mark M, Selmic, Laura E, Everitt, Jeffrey I, Mccall, Shannon J, Eward, Cindy, Eward, William C, Hsu, S David
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 21.10.2020
Subjects
Bone cancer
Conflicts of interest
Cytotoxicity
Drug discovery
Drug screening
Nuclear transport
Osteosarcoma
Proteasomes
Xenografts
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Summary:Abstract Purpose 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. Experimental design 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 experimental framework and set of new tools for osteosarcoma and other rare cancers to identify and study new therapeutic vulnerabilities. Competing Interest Statement The authors have declared no competing interest. Footnotes * Conflict of interest statement: The authors declare no conflicts of interest.
DOI:10.1101/2020.10.19.346387