Canine models for characterization, diagnosis, and treatment of human cancers using comparative canine-human transcriptomics

National Center For Advancing Translational Sciences

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Abstract

We previously identified 262 tissue-expressed proteins associated with particular cancers (lung adenocarcinoma, melanoma, osteosarcoma, B- and T-cell lymphoma), leading to identification of a set of 60 approved drugs known to affect the expression of said proteins. Single-compound cell-based screens identified 40 drugs with cancer cell-killing effects, while subsequent matrix screens identified a set of 20 two-drug combinations that exhibited synergy in cancer cell-killing experiments. In preparation for testing in patient-derived xenograft (PDX) mouse models of various cancers, the 20 drug combinations are currently being confirmed against canine and human cancer cell lines consistent with those used in the mouse PDX models in the NCI repertoire. Although studies are ongoing, several drug combinations have recapitulated the expected synergistic activity. These and other drug combinations confirmed to exhibit synergistic activity will then be tested in vivo. Those found to be active in the PDX mice will be further interrogated in clinical trials on patient dogs with the relevant cancers. Those drug combinations found to be effective in these canine studies will inform the design of future clinical studies in humans. In a parallel effort, canine osteosarcoma (OSA) transcriptomics data were used to test a human OSA prognosis in silico model. This human model successfully predicted prognosis in dogs, validating the comparative oncology approach for OSA (Mannheimer et al., Communications Biology, 2023). Refinement of the model revealed that immunologically active tumors showed better prognosis than immunologically inactive tumors in both human and dog. These results indicate that immune therapy strategies are likely to be useful in human OSA and that dogs should serve as a valid model to develop such therapies.