Grantee: Washington University in St. Louis, Saint Louis, MO, USA
Researcher: David H. Gutmann, M.D., Ph.D.
Grant Title: Development of preclinical mouse models of meningioma
Program Area: Researching Brain Cancer
Grant Type: Research Award
Amount: $300,000
Year Awarded: 2004
Duration: 3 years
Brain tumors are one of the most devastating forms of cancer. The options for treatment are limited. Sadly, many brain tumors are fatal.
The most common brain tumors are the glioma and the meningioma. Scientists know a lot about gliomas, but not much about how meningiomas form.
Meningiomas are slow growing tumors that are attached to the dura, a covering that surrounds the brain. These tumors are common in people in their sixties and seventies, particularly in women. Although most are benign cancers, meningiomas can grow into the brain, spread along the dural covering, and even metastasize to the lungs, liver and bone. Meningiomas often develop in people who have been exposed to radiation. Aggressive surgery is currently the best treatment. No chemotherapy has been proven effective.
Since people who have the inherited cancer predisposition syndrome, neurofibromatosis 2 (NF2). frequently develop meningioma, scientists have focused their attention on whether the NF2 gene plays a role in meningioma formation. Inactivation of the NF2 tumor suppressor gene is the most frequently detected genetic alteration in meningiomas. The NF2 gene is a member of the Protein 4.1 family of membrane-associated proteins. Recently, our laboratory has identified two additional Protein 4.1 tumor suppressor genes, 4.1B and 4.1R, that are also inactivated in meningiomas.
To find out how important the NF2 gene is in the formation of meningiomas, we used a specially designed virus to inactivate the NF2 gene in meningeal cells in the dural brain lining of mice. We found that when NF2 expression was lost, meningiomas formed. Our NF2 mouse model represents a significant advance as the first and only small animal meningioma model. However, the frequency of meningioma formation is low, and there are some serious limitations with the viral NF2 inactivation approach we used. If we could develop a better model, the entire community of meningioma researchers could move forward and answer questions that have challenged scientists for many years.
Based on our encouraging initial discoveries, we have initiated an international collaborative research program to develop robust preclinical mouse models of meningioma. In this proposal, we have three specific objectives. First, we will employ several additional strategies to generate mice that develop meningioma at higher frequency. In these studies, we will generate two strains of genetically-engineered mice that can be used to inactivate certain tumor suppressor genes in meningeal cells. We will use these new mouse strains to inactivate the NF2 or 4.1B gene specifically in meningeal cells. This will allow us to develop mouse models for the two most common genetic abnormalities in human meningiomas. Second, we propose to generate mice in which combinations of genetic alterations will be introduced in meningeal cells in living animals. This will allow us to develop mouse models of high-grade malignant meningioma. Lastly, the ultimate goal of these studies is to generate mouse models of meningioma that are suitable for evaluating potential chemotherapies. In this regard, we will study benign and malignant mouse meningiomas using brain magnetic resonance imaging (MRI). At Washington University, we have access to one of the finest imaging centers in the world. We will collaborate with our colleagues in the University’s Mallinckrodt Institute of Radiology, which houses two dedicated state-of-the-art small animal MRI machines.
If we are successful in accomplishing these ambitious goals, the genetically engineered mouse strains we create for benign and malignant meningiomas will afford us—and scientists elsewhere who grapple with the same issues—the unique opportunity to begin translational research studies. We will be able to evaluate the clinical behavior of these tumors in mice, identify additional meningioma therapeutic targets for future drug design, and evaluate potential meningioma therapies. The availability of these genetically engineered mice will greatly accelerate the development and assessment of potential therapies for this important brain cancer in humans.