Comparative Response of Canine and Human Osteosarcoma Tumour Cell Lines to Molecularly Targeted Anticancer Agents at Clinically Relevant Exposures With Analysis of Genomic Biomarkers.
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Osteosarcoma (OSA) is a primary bone tumour occurring in children but is also prevalent in large breed dogs. Canine OSA (cOSA) has long been viewed as analogous to human OSA (hOSA) with cOSA serving as a surrogate for development of therapeutic approaches to treat the rarer human form. Drug therapy of OSA has remained virtually unchanged over the last four decades and drug testing is challenging due to the genomic heterogeneity of OSA as well as the limited number of patients for clinical trials. Thus, an approach that includes a suitable clinical surrogate at the early stage of therapeutic development may be beneficial. Therefore, to address these challenges, a phenotypic drug screen of 12 targeted anticancer drugs was carried out using 13 cOSA and 6 hOSA cell lines and responses compared at clinically relevant exposures (CRE) estimated from human data. The results identified four drugs (alisertib, crizotinib, onvansertib and sorafenib) with significant responses at the CRE in cOSA and hOSA cell lines and demonstrated that drug responses were indistinguishable across species. Correlations of drug response with genomic biomarkers in the cOSA cell line panel identified Myc and Hedgehog signalling as potential predictors of crizotinib response and Myc, epithelial markers and anti-apoptotic signalling for onvansertib response. The conclusions of these findings are that cOSA and hOSA cell lines show the same range of response to targeted agents and identify potential biomarker pathways for further investigation in OSA tumours for use in future comparative oncology studies including clinical trials in pet dogs.