The high attrition rate of compounds entering clinical testing as potential anticancer drugs indicates a need for better methods to predict efficacy before testing in humans.
The poor correlation between therapeutic activity of compounds tested in xenograft mouse models and their efficacy in humans does not necessarily mean that more faithful genetically engineered mouse models (GEMMs) will be of limited use in drug development.
Indeed, a major untapped solution could lie in the use of refined GEMMs of human cancer that are capable of facilitating the identification of the right target, the right drug and the right patients.
The attributes of a 'well-designed' GEMM include moderate penetrance and short latency of single tumours, engineered alleles that are representative of the human disease, and simplicity in colony management and technical use.
There are several important applications for GEMMs in anticancer drug development, including target validation, assessment of tumour response, investigation of pharmacodynamic markers of drug action, modelling resistance and understanding toxicity, which are discussed in this article.
Deficiencies in the standard preclinical methods for evaluating potential anticancer drugs,such as xenograft mouse models, have been highlighted as a key obstacle in the translation of the major advances in basic cancer research into meaningful clinical benefits. In this article, we discuss the established uses and limitations of xenograft mouse models for cancer drug development, and then describe the opportunities and challenges in the application of novel genetically engineered mouse models that more faithfully mimic the genetic and biological evolution of human cancers. Greater use of such models in target validation, assessment of tumour response, investigation of pharmacodynamic markers of drug action, modelling resistance and understanding toxicity has the potential to markedly improve the success of cancer drug development.
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We thank P. Nisen, K.-K. Wong, K. Anderson, D. Hanahan, D. Frost, G. Gordon, A. Shoemaker and S. Mellis for stimulating discussions and critical reading of the manuscript. R. A. D. is an ACS Research Professor and an Ellison Medical Foundation Senior Scholar. This work was supported by grants from the Sidney Kimmel Foundation for Cancer Research (N.E.S.), the Ellison Medical Foundation (N.E.S. and R.A.D.) and the National Institutes of Health. R.A.D. is supported by the LeBow Fund to Cure Myeloma and the Robert A. and Renee E. Belfer Foundation Institute for Innovative Cancer Science.
R.A.D. is a director, co-founder and scientific advisor of AVEO Pharmaceuticals, Inc., which develops and uses mouse models of human cancer, including GEMMs and xenotransplants; R.A.D. also serves on the cancer scientific advisory council of Abbott Pharmaceuticals. The views expressed by R.A.D. are his own and do not reflect those of the management of AVEO or Abbott Pharmaceuticals.
- Xenograft model
Xenograft mouse models of cancer are created by injecting homogeneous human tumour cell lines into immunodeficient (for example, severe combined immunodeficiency) mice.
- RECIST Criteria
Response Evaluation Criteria in Solid Tumors are standardized, radiographic criteria for determining tumour response or progression in human clinical trials of cancer therapeutics.
- CRE recombinase
A phage enzyme that is used in murine genetic engineering. Expression of the enzyme causes selective excision of all genetic material between two LoxP sites. Murine strains can be engineered with LoxP sites flanking a gene of interest, stop codon and so on, and expression of CRE in these strains allows for tissue-specific and inducible changes in gene function.
The ability to regulate gene expression by feeding engineered murine strains tetracycline analogues (for example, doxycycline). Mice are engineered to contain a transgene of interest that is either induced (tet-ON) or repressed (tet-OFF) in the presence of doxycycline. These strains allow for the study of tissue-specific and inducible changes in gene expression. An advantage of tet-regulation is that the gene of interest can be serially induced and repressed by withdrawing and adding doxycycline to the animal's drinking water.
- Oncogene addiction
The notion that cancer cells strictly require the activity of certain mutant oncogenes (for example, BCR–ABL in chronic myelogenous leukaemia), and therefore these oncogenes are required for tumour maintenance and are desirable therapeutic targets.
- Metronomic therapy
Continuous or frequent treatment with low doses of cancer therapeutics, often given in a schedule-dependent manner with other methods of therapy. The goal is to inhibit an important cancer-relevant process (for example, angiogenesis) with minimal toxicity.
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Sharpless, N., DePinho, R. The mighty mouse: genetically engineered mouse models in cancer drug development. Nat Rev Drug Discov 5, 741–754 (2006). https://doi.org/10.1038/nrd2110
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