Abstract 2933: Application of a mouse model humanized for the major pathways of drug disposition in anticancer drug development and use

• Published in: Cancer research (Chicago, Ill.) Vol. 79; no. 13_Supplement; p. 2933
• Main Authors: Henderson, Colin J., Scheer, Nico, Kapelyukh, Yury, McLaren, Aileen, MacLeod, Kenneth, Rode, Anja, Lin, De, Wolf, C Roland
• Format: Journal Article
• Language: English
• Published: 01.07.2019
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2019-2933

Abstract A vast number of targeted anticancer drugs are being developed in the pharmaceutical industry whose efficacy will only become fully realized through their combination with other established or novel anti-tumor agents. This is particularly the case because combination chemotherapy is a major approach being taken to overcome the rapid onset of drug resistance which current dosing regimens can cause. This has raised the conundrum of which of the large number of possible drug combinations, which may involve combinations of more than two drugs, have the greatest chance of success. It is not possible to test all the possible combinations by clinical trial alone so more informative preclinical models are badly needed. Nearly all targeted anti-tumor agents are substrates for the cytochrome P450-dependent monooxygenase system. The testing of novel drug regimens in mice is severely compromised by the major species differences in this enzyme system both in catalytic function, in the pattern of metabolite formation and the regulation by transcription factors such as CAR and PXR. In order to circumvent this problem we have created a mouse model where thirty four murine P450’s have been deleted from the mouse genome and substituted for the major enzymes involved in drug disposition in man ie CYP1A1, CYP1A2, CYP2C9, CYP2D6, CYP3A4 and CYP3A7. The mice have also been humanized for the transcription factors CAR and PXR. CYP3A4 and CYP2D6 are expressed off the human promoters. We report the validation the utility of this model by studying the in vivo metabolism and disposition of model drugs and the metabolism and disposition of the EGFR inhibitor, osimertinib and the BRAF inhibitor, dabrafenib. We show that the use of this model allows accurate prediction of clinically observed drug exposures, in the generation of human metabolites and drug/drug interactions. This model has therefore great potential for the development of combination therapies involving complex drug regimens and in the design of clinical trials targeted at overcoming drug resistance. Citation Format: Colin J. Henderson, Nico Scheer, Yury Kapelyukh, Aileen McLaren, Kenneth MacLeod, Anja Rode, De Lin, C Roland Wolf. Application of a mouse model humanized for the major pathways of drug disposition in anticancer drug development and use [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2933.