Mouse Models of Advanced Spontaneous Metastasis for Experimental Therapeutics

Abstract

An enduring problem in cancer research is the failure to reproduce highly encouraging preclinical therapeutic findings using transplanted or spontaneous primary tumours in mice in clinical trials of patients with advanced metastatic disease. There are several reasons for this, including the failure to model established, visceral metastatic disease. We therefore developed various models of aggressive multi-organ spontaneous metastasis after surgical resection of orthotopically transplanted human tumour xenografts. In this Opinion article we provide a personal perspective summarizing the prospect of their increased clinical relevance. This includes the reduced efficacy of certain targeted anticancer drugs, the late emergence of spontaneous brain metastases and the clinical trial results evaluating a highly effective therapeutic strategy previously tested using such models. Limited value of mouse therapy models Preclinical tumour models are a fundamental component of the study and design of new regimens for cancer treatment. Nonetheless, there are considerable shortcomings in the models used, both past and present. To cite just a few examples, tumour cell lines implanted subcutaneously in mice generally tend to grow rapidly and thus do not mimic the much slower doubling times of most human cancers. This may render them, for example, much more sensitive to most chemotherapy drugs that target dividing cells. It is also unclear whether ectopic (out of the normal place) subcutaneously implanted tumours-still a standard methodology-will respond to a therapy in the same way if grown in an orthotopic site 1 (in their organ or tissue of origin, such as breast cancers in mammary fat pads). In addition, tumour-bearing mice are often treated with drugs at levels, or with pharmacokinetics, that are not relevant to humans 2-4. Furthermore, almost all the preclinical models that have been studied have not involved tumours that were pre-exposed to another therapy, whereas many Phase I and Phase II clinical trials involve patients who have already undergone and progressed under first, second, or even more therapies and to which their tumours have become refractory. In addition, these models fail to reflect Phase I, Phase II and most Phase III clinical trials of patients with advanced metastatic disease in multiple