A Comparative Oncology Drug Discovery Pipeline to Identify and Validate New Treatments for Osteosarcoma

Simple Summary Osteosarcoma is a rare bone cancer that occurs primarily in children. The discovery of new treatments for osteosarcoma and other rare cancer types has been severely limited by access to patient samples to study these often-complex diseases. Here we capitalize on naturally-occurring cancers in pet dogs to study the biology of these rare cancers. Using living cells from canine and human patients to test thousands of drugs simultaneously, we identify a unique combination of drugs that disrupts protein degradation and protein trafficking in cancer cells. This drug combination represents a promising new treatment to treat both dogs and people with osteosarcoma. 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 experimental framework and set of new tools for osteosarcoma and other rare cancers to identify and study new therapeutic vulnerabilities.