Funded Grants

Molecular evolution of a brain tumor: Analysis of pre-tumor cells in a mouse model of medulloblastoma

Medulloblastoma, a tumor of the cerebellum, is the most common type of malignant brain tumor in children. It occurs most frequently between 5 and 10 years of age, and accounts for 20-30% of all pediatric brain tumors. Medulloblastoma is an extremely aggressive tumor, and is usually treated with a combination of surgery, radiation and chemotherapy. While these approaches are often effective at shrinking the primary tumor, recurrence and metastasis are common, and only 50% of medulloblastoma patients survive for 5 years after diagnosis. Even survival may be a mixed blessing, since treatment of children with radiation and chemotherapy can often impair intellectual and physical development and increase the risk of other cancers later in life. New approaches to the treatment of medulloblastoma are clearly necessary, and may only come from a deeper understanding of the genetic basis of this disease.

An important step towards understanding the molecular basis of medulloblastoma has come from studies of a gene called patched. Patched normally functions to inhibit the proliferation of cells in the cerebellum, and when it is mutated cells may proliferate too much. In fact, many people with medulloblastoma have mutations in patched, suggesting that this gene plays an important role in tumor formation. Moreover, mice with patched mutations develop tumors that resemble human medulloblastoma, and have become an important model for studying the disease. But having a mutation in patched does not necessarily mean that one will develop medulloblastoma: only 15% of patched mutant mice (and only 3-5% of people with mutations in this gene) end up developing tumors. These findings suggest that other genes besides patched must be involved in the formation of medulloblastoma.

In order to identify these genes, we will take advantage of a unique property of patched mutant mice. Although only 15% of these animals develop brain tumors, about 50% have patches of abnormal cells in their cerebellum. These cells resemble medulloblastoma cells in their location and appearance, but have not yet acquired all the characteristics of medulloblastoma. By studying these "pre-tumor cells" we can learn about the earliest and most critical changes that are necessary for a normal cell to develop into a medulloblastoma.

In this application we propose to isolate pre-tumor cells from patched mutant mice and determine how they differ from normal cells and from tumor cells. We will examine the behavior of pre-tumor cells in culture, to determine whether they have defects in the ability to control proliferation or in the ability differentiate or die. In addition, we will identify the genes that change as normal cells develop into pre-tumor cells and then into tumors, since these genes are likely to play critical roles in medulloblastoma formation. To test the importance of these genes, we will introduce them into normal animals and see if they cause brain tumors. Genes that do promote tumor formation in mice would be good candidates for genes that are mutated in human medulloblastoma, and might represent important new targets for medulloblastoma therapy. By understanding the function of these genes and developing ways to specifically disrupt them, we hope to contribute to the development of more effective treatments for medulloblastoma.