Modeling Therapy of Late or Early‐Stage Metastatic Disease in Mice

Abstract

Overview An ongoing problem in oncology drug development is the frequent failure of preclinical therapy models involving treatment of tumor‐bearing mice, which show positive results, to predict similar success in patients enrolled in clinical trials. There are numerous possible reasons for causing such high rates of false positives. One is the failure to reproduce the clinical circumstances of treating systemic metastatic disease, whether microscopic or macroscopic in nature—but especially the latter. Thus, it is still common practice to treat mice with established primary tumors, whether they are transplanted or spontaneous, of mouse or human origin, or derived from cell lines or tumor tissue grafts—including human patient‐derived xenografts (PDXs). In this chapter, we summarize recent progress in developing mouse models of spontaneous metastases, especially of late‐stage disease, after surgical resection of primary tumors, including the use of human tumor cell lines, PDXs, and genetically engineered mouse models (GEMMs). Some limited therapy results using such models, and how they retrospectively or prospectively correlated with relevant phase III clinical trial outcomes, are discussed. A limited database indicates the possible benefits of using such models for predictive investigational therapeutic studies relevant to the treatment of patients with metastatic disease. Some limitations of such models are also discussed.