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Mouse Models of Human Cancers Consortium:
Modeling Human Cancers in the Mouse

About Mouse Models

Animal models - laboratory animals that have specific characteristics resembling a human disease or disorder - play an invaluable role in cancer research. Technologies available today allow scientists to create animal models of cancer by transferring new genes into animals or inactivating certain existing genes. This makes the animals susceptible to specific cancers via the same genetic and environmental factors that affect humans. With these models, scientists can:

• Study the biological changes associated with every stage of tumor development.
• Test new approaches to detection and diagnosis.
• Evaluate prevention and treatment strategies.

For a variety of reasons, mice are particularly well suited for cancer research. To start, mice and humans are similar in their genetic makeup and susceptibility to cancer. As a result, the development of tumors in mice largely parallels that in humans. Further, mouse tumors develop over the course of months rather than the years usually required for cancer to develop in larger animals and humans.

But the complexity of cancer makes the development of mouse models a far more challenging task for cancer than for some other diseases.

Fortunately, cancer researchers today have a wide range of resources to bring to bear on this task. Scientists have access to:

• Increasingly detailed databases containing the details of mouse and human genes
• A growing body of information on the molecular characteristics, or signatures, of tumors

This expanding knowledge - coupled with tools for modifying the genes of laboratory mice and a battery of tests to identify relevant cancer genes and proteins - ensure that cancer mouse models parallel the development, progression, and clinical course of human cancers.

Created by NCI in late 1999, the Mouse Models of Human Cancers Consortium involves 20 multidisciplinary groups of investigators in improving the pace and efficiency with which mouse models of cancer are developed and tested, and to ensure they are readily available to scientists. Consortium scientists are working to develop and evaluate mouse models for breast, prostate, lung, ovary, cervix, pancreas, skin, blood and lymph system, colon, and brain cancers.

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How Mouse Models Are Advancing Cancer Research

Throughout the Consortium and in other NCI-supported laboratories, researchers are using mouse models to examine the interplay of genetic and environmental factors in cancer susceptibility, test novel approaches to detection, diagnosis, and imaging, and advance the use of genetically engineered mice for prevention, therapy, and population research.

Mouse models provide a unique opportunity to explore how genetic and environmental factors interact to give rise to cancer. With such models, scientists can test the effects of a particular chemical in a controlled environment using animals with a known genetic makeup.

For example, researchers are using a recently developed mouse model of lung cancer to:

• Investigate the role that genetic factors play in determining why some smokers develop lung cancer and others do not.
• Test whether tobacco smoke accelerates tumor formation.
• Define the genes that confer susceptibility to tobacco-related cancers.

Because samples of human cancers at their earliest stages can be difficult to obtain, mouse models also are invaluable in cancer detection studies. Tumors in these mice can be examined to verify the role that each genetic alteration plays in causing cancer and in its progression, and may also reveal changes informative to human cancer diagnosis or early detection.

An example of this type of research is a newly developed mouse model that closely mimics inflammatory bowel disease, a condition associated with increased cancer risk. Researchers are using this model to test the effect of known and suspected causal factors - such as the Helicobacter bacteria - on the timing and severity of cancer. By taking biopsies at varying times after infection, they are looking for the earliest changes indicating increased risk for gastric, intestinal, or colon cancer.

Defining the changes associated with cancer also is fundamental for finding potential targets for early intervention. Once these targets have been identified, scientists depend on mouse models to test the efficacy of new drugs, and to understand why a drug does - or does not - work as expected. Indeed, one of the most important roles of mouse models is in the development of drugs to treat cancer.

In one recent example of using mouse models to test treatments, investigators used a model of one type of childhood leukemia to help solve the mystery of why some children respond to the standard therapy of retinoids while others do not. As they studied the problem in the model, scientists discovered that the mice that did not respond to treatment had an unexpected gene rearrangement. With this information, the researchers then developed a new treatment that blocks the action of the rearranged gene. It was effective in combination with retinoids in mice, and these investigators are now assessing the combined treatment in childhood leukemia patients who do not respond to retinoid therapy alone.

Models also are valuable for studying a host of treatment questions, such as determining mechanisms of drug resistance and defining new treatment targets.

With specialized equipment and techniques for imaging mice and other small animals, investigators are using mouse models to explore improvements in cancer imaging and treatment in order to determine whether anti-cancer drugs have reached their targets and to track response to therapy. Since 1999, much of this research has been fostered by Small Animal Imaging Resource Programs that NCI has established at a number of research centers around the country.

As Consortium investigators develop more mouse models of cancer, collaborations among them and small animal imaging specialists are expected to grow. Already, Consortium scientists involved in developing mouse models for prostate cancer have teamed with colleagues from the NCI-funded Small Animal Imaging Resource Program to use positron emission tomography imaging to study prostate cancer development, from its beginnings in the prostate to its metastasis (spread) to bones and other organs.

Similarly, investigators testing mouse models of brain tumors are collaborating with small animal imaging experts to use magnetic resonance imaging to test approaches to gene therapy for brain tumors. Experiments of this kind are already revealing new avenues for human therapy.

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The Future of Mouse Models

If the research community is to employ mouse models to their greatest advantage, extensive collaborations are needed among those who can best inform the design of the models and their ultimate use in cancer research. NCI is facilitating the formation of collaborative groups - e.g., for ovarian, brain, pediatric, and pancreatic cancer modeling - to ensure rapid incorporation of human cancer research discoveries into mouse model design and application.

With NCI's help to organize conferences and symposia, Consortium investigators are spearheading the dissemination of information about:

• Mouse engineering tactics
• Development of validation standards for cancer models
• The practical application of models to inform many aspects of cancer research

The achievements of Consortium investigators and the need to deploy models to the research community prompted NCI to establish the Mouse Models of Human Cancers Consortium Mouse Repository, to which interested scientists are invited to contribute models.

When it opened in February 2001, the NCI repository had three mouse strains available for distribution. The number of mouse models offered is expected to quickly increase, reaching at least 30 by early 2002. NCI will expand the repository in the future to accommodate the growing requirements of the cancer research community for well-designed and thoroughly tested mouse models.