Applications of patient-derived tumor xenograft models and tumor organoids

Go J Yoshida

doi:10.1186/s13045-019-0829-z

Abstract

Patient-derived tumor xenografts (PDXs), in which tumor fragments surgically dissected from cancer patients are directly transplanted into immunodeficient mice, have emerged as a useful model for translational research aimed at facilitating precision medicine. PDX susceptibility to anti-cancer drugs is closely correlated with clinical data in patients, from whom PDX models have been derived. Accumulating evidence suggests that PDX models are highly effective in predicting the efficacy of both conventional and novel anti-cancer therapeutics. This also allows “co-clinical trials,” in which pre-clinical investigations in vivo and clinical trials could be performed in parallel or sequentially to assess drug efficacy in patients and PDXs. However, tumor heterogeneity present in PDX models and in the original tumor samples constitutes an obstacle for application of PDX models. Moreover, human stromal cells originally present in tumors dissected from patients are gradually replaced by host stromal cells as the xenograft grows. This replacement by murine stroma could preclude analysis of human tumor-stroma interactions, as some mouse stromal cytokines might not affect human carcinoma cells in PDX models. The present review highlights the biological and clinical significance of PDX models and three-dimensional patient-derived tumor organoid cultures of several kinds of solid tumors, such as those of the colon, pancreas, brain, breast, lung, skin, and ovary.

Highlights

Since the first investigations to develop drugs using animal models of leukemia were reported in 1950 [1], many types of murine models transplanted with human tumors have been developed to predict responses to chemotherapy
Combination treatment with cetuximab and pimasertib induced a complete response, in which tumor tissues remained undetectable for more than 6 months. These findings suggested that combination treatment is highly likely to inhibit development of resistant tumors with intra-tumoral heterogeneity, and highlighted the utility of patient-derived tumor xenografts (PDXs) models in establishing highly effective treatment regimens
Because insulin growth factor 1 receptor (IGF1R) is highly expressed in both pancreatic cancer cells and stromal fibroblasts, Zhou et al developed nanoparticles with recombinant human IGF1 conjugated to magnetic iron oxide carrying anthracycline doxorubicin (IGF1-IONP-Dox), and demonstrated an enhanced therapeutic effect compared with conventional Dox treatment in the orthotopic pancreatic ductal adenocarcinoma (PDAC) PDX model

Summary

Introduction

Since the first investigations to develop drugs using animal models of leukemia were reported in 1950 [1], many types of murine models transplanted with human tumors have been developed to predict responses to chemotherapy. These tumor-derived organoids have emerged as pre-clinical models that have the potential to predict personalized response to treatment. Breast carcinoma PDX models maintain the essential properties of the original patient tumors, including metastatic tropism, suggesting their physiological relevance for study of human cancer metastasis [4].

Results

Conclusion