Funded by the National Cancer Institute since 2000, the NCI-Mouse Models of Human Cancers Consortium (NCI-MMHCC) has significantly advanced the science of in vivo and in vitro cancer modeling by deriving cancer-prone models through altering germlines of laboratory mice, developing a variety of organotypic co-culture systems, and grafting human tissues into immuno-compromised mice. The 25 groups who comprise the Consortium  more than 300 members at 50 institutions, including the NCI center for Cancer Research in the US and abroad  are expert in many aspects of basic, translational, and clinical cancer research, in engineering the mouse germline to simulate human cancers, and in using inbred mouse strains as models for human cancer susceptibility.

The newest genetically engineered mouse models (GEMMs) are excellent simulations of the corresponding human diseases. The NCI-MMHCC grant projects provide in-depth information about the molecular, biologic, and functional properties of the many models, and devise new ways to cross-compare the models to human cancers. These projects have produced important discoveries about biological markers that distinguish among previously unrecognized patient groups. This provides better patient stratification for application of new therapy combinations, and identifies potential novel secondary and additional targets. These models foster discoveries about the nature of cells-of-origin and cancer stem cells for many organ sites, the biology of cancer initiation and tumor progression, and the genetic basis of cancer susceptibility and response or resistance to therapy. The increasing use of many modalities of in vivo imaging of GEMMs disclose functional and molecular changes during cancer initiation, progression, invasion, metastasis, and response to therapy, heralding a new era of discovery for early detection and for identifying surrogate markers of response.

The Consortium cooperates with the NCI to evolve a comparative medicine approach to human cancer research, and with the NCI Center for Bioinformatics to provide the databases and bioinformatics infrastructure to integrate cancer model information with comparable human disease data. One trans-Consortium project is the Pre-Clinical Testing Demonstration to focus development of an experimental therapeutics infrastructure; all of the participating laboratories use the same agent and protocol on a number of GEMMs and other models. The project tests efficacy differences across tumor types, identifies key biomarkers of response, examines whether these are context dependent, determines reproducibility of the protocol across models and testing sites, evaluates the design and performance of the preclinical testing informatics infrastructure, test specific research hypotheses using one or more analyses, and determines if novel conclusions can be derived from aggregated analyses. The conduct of this pilot project has attracted unprecedented interest from pharmaceutical and biotechnology companies, enabling the Consortium to develop partnerships with the private sector to define when, where, and how GEMMs contribute to the discovery-development-delivery continuum that leads to derivation of novel agents for cancer.

 

No research challenge for cancer embraced by the NCI-MMHCC is more important than that of experimental therapeutics. The Consortiums collaboration with the NCI to evolve an experimental therapeutics infrastructure eventually will enable full integration of preclinical science and agent testing with NCI-sponsored clinical trials. An integrated infrastructure will permit the development of appropriate imaging strategies and nanotechnology delivery systems, and discovery of surrogate markers prior to the initiation of clinical trials. Possible outcomes of this integrated approach will be improved prognostic information and reliable means to define better when to discontinue a particular treatment. An effective experimental therapeutics infrastructure will rely heavily on bioinformatics support that is integral with the NCI's caBIGJ clinical trials infrastructure. The LIMS for capturing individual animal testing data and demographics enables integration of the preclinical data with caBIGJ, and with the Cancer Models and Cancer Images databases, which are public information resources. Another resource, the NCI Mouse Repository deploys fully developed mouse cancer models and "tool" strains free-of-charge to scientists worldwide.

 

Since its inception in 2000, the NCI-MMHCC has created connections to many NCI-and NIH-funded programs. Embedded in the Consortium are collaborations with the NCIs SPORE program, Early Detection Research Network, Cancer Genetics Network, Cancer Family Registries, Clinical Proteomic Technology Assessment Centers, Centers of Cancer Nanotechnology Excellence, Chemopreventive Agent Development Research Group, and Integrative Cancer Biology Program. The Consortium also has ties to the NCRR-funded Biomedical Informatics Research Network and international network of mouse repositories, or IMSR.