Effective Utilization and Appropriate Selection of Genetically Engineered Mouse Models for Translational Integration of Mouse and Human Trials

Abstract

The landscape of cancer research and therapy has radically changed over the past decades in at least two major respects: Our ability to model cancer in the mouse has risen to an unprecedented level of accuracy at the same time that novel cancer drugs have been developed in record numbers. This has led to an explosion in genetically engineered mouse model (GEMM) research, as GEMMs can potentially be used to test and optimize drugs in a variety of ways: preclinically (before testing in human patients), coclinically (in parallel with human testing), and postclinically (to optimize standard of care therapy). Thus the potential applications of faithful GEMMs of cancer have expanded from analysis of causal relationships between genetic aberrancies and tumorigenesis in preclinical efforts to a more comprehensive and systematic utilization of GEMMs for drug testing and clinical trial optimization. As GEMM research has grown, however, few standard protocols have been put in place regarding GEMM trials done in parallel with human trials (the “coclinical” approach), or in situations in which the available cohort of human patients is too small for valid statistical analysis. The success of such efforts will require an increased attention to the rigor with which mouse and human clinical efforts are designed, executed, and integrated.