Harnessing preclinical mouse models to inform human clinical cancer trials

Abstract

The urgent need for better cancer treatments has stimulated interest in employing small-animal models to evaluate potential drug therapies. Robust mouse models of many human cancers have been generated using sophisticated technologies for engineering germ-line mutations. As we enter into an age of targeted therapeutics, these strains provide novel platforms for validating new anticancer drugs, assessing therapeutic index, identifying surrogate markers of tumor progression, and defining epigenetic and environmental influences on tumorigenesis.The availability of strains of genetically engineered mice (GEM) that develop a spectrum of cancers similar to those found in humans offers an unprecedented opportunity to efficiently evaluate the efficacy and therapeutic index of novel anticancer therapies in preclinical models in advance of human trials. While straightforward in principle, executing preclinical studies in mice that allow for meaningful and immediate application to the treatment of human cancer is difficult. Moreover, the potential use of GEM cancer models to accelerate the process of bringing effective new treatments to patients is largely theoretical, as few examples exist in which mouse preclinical data has been successfully translated to clinical practice. The current development process for anticancer drugsTaking a drug from discovery to market is an arduous process that frequently takes longer than 15 years and costs more than $800 million. Most agents that are advanced into early-phase human clinical trials fail. Recent advances in the fields of cancer biology and high-throughput screening have identified numerous potential molecular targets for drug discovery; however, most of the proteins and pathways deregulated in cancer cells also have essential roles in normal cells. It is therefore difficult to predict when a drug will prove tumor-selective. Moreover, developing new therapies against specific molecular abnormalities in well-defined subsets of cancers can be prohibitively expensive. The use of GEM cancer models as an initial "filter" to identify tumors and molecular targets that, when inhibited, will selectively kill tumor cells is one potential strategy for streamlining the overall process of cancer drug development. Preclinical mouse models of human cancerNumerous small-animal models of human cancer have been generated. These include inbred strains that spontaneously develop cancer (1-4), rodents in which cancer is caused by intrauterine or postnatal exposure to chemical mutagens (5-9), and mice in which tumors are produced by viral or bacterial infection (10-13). In addition, xenograft models that were generated by directly implanting cancer cell lines established from human tumors into mice have been widely used for drug discovery (14-17). The major limitations of these explant models are the requirement for an immunocompromised host and the inability of these models to fully recapitulate the complex relationship between the tumor and its microenvironment (e.g., angiogenesis). Most importan...

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