Abstract
Experimental animal tumor models have been broadly used to evaluate anticancer drugs in the preclinical setting. They have also been widely applied for drug target discovery and validation, which usually follows four experimental strategies: first, assess the roles of putative drug targets using in vivo tumorigenicity and tumor growth kinetics assays of transplanted tumors, engineered through gain-of-function (GOF) by overexpressing transgene or knock-in (KI) or loss-of-function by gene silencing using knockdown (KD) or knockout (KO) or mutation via mutagenesis procedures; second, similarly genetically engineered mouse models (GEMM), through either germline or somatic cell procedures, are used to test the roles of potential targets in spontaneous tumorigenicity assays; third, patient-derived xenografts (PDXs), which most closely resemble patient genetics and histopathology, are used in tumor inhibition assays for evaluating target-/pathway-specific inhibitors, including large and small molecules, thus assessing the drug target; and fourth, the targets can be assessed in population-based trials, mouse clinical trials (MCT), so that the validation can be generally meaningful as performed in human clinical trials. This chapter outlines the commonly used protocols in cancer drug target research: the first four sections describe four sets of different, specific pharmacology protocols used in the respective cancer modeling stages, with the last section summarizing the common protocols applicable to all four pharmacology modeling steps.
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Acknowledgments
The authors would like to thank all the members of the Translational Oncology Division, Crown Bioscience, Inc. for their dedicated work in cancer animal modeling over the last decade, which contributes to many of these protocols. The authors would also like to thank Dr. Jody Barbeau for careful reading and editing of this manuscript and Mr. Ralph Joseph Manuel for some of the artworks. Dawei Chen and Xiaoyu An contributed equally to this work.
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Chen, D., An, X., Ouyang, X., Cai, J., Zhou, D., Li, QX. (2019). In Vivo Pharmacology Models for Cancer Target Research. In: Moll, J., Carotta, S. (eds) Target Identification and Validation in Drug Discovery. Methods in Molecular Biology, vol 1953. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-9145-7_12
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DOI: https://doi.org/10.1007/978-1-4939-9145-7_12
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