Drug Development Based on Intracellular Pharmacokinetic Analysis of Molecular Target Drug in Mice Bearing Patient-derived Xenograft Model

Abstract

Traditionally, anticancer drug discovery research has been conducted based on immortalized cancer cell lines, either cultured in vitro or grown in vivo. In the USA and Europe, patient derived xenograft (PDX) model is rapidly expelling traditional in vitro and in vivo models due to the good predictability of clinical outcome and its nature of retaining characteristics and heterogeneity in the original tumor. Furthermore, a significant association was also reported between drug responses in patient and corresponding PDX as high as 87%. We are preparing a PDX model for Japanese cancer patients including drug resistance examples and rare cancers. Using the established PDX model, we confirmed the possibility that the tumor microenvironment might affect the efficacy and distribution of drugs even if the target receptor is expressed in tumor sites as compared to the cell line (CDX) model, which has been widely used in drug discovery. Interestingly, although expressing a target receptor in viable tumor cells, we also have found a PDX model with a lower distribution of molecular target drug. Therefore we will evaluate the usefulness of the PDX model in drug development by exploring new biomarkers and elucidating the mechanisms of drug resistance in target tumors. Moreover, pharmaco-imaging system will allow us to visualize the exposure and distribution of drugs in tumors at macro and micro levels. Finally, we evaluate relations between distribution of drugs in the tumor microenvironment including target tumor cells, neovessels, stromal cells, immune cells, and fibroblasts.