MDM2 as an Effector of Hedgehog Signaling in Brain Development and Medulloblastoma

Background
Medulloblastoma (MB), a tumor of the cerebellum, is the most common malignant brain tumor in children. Despite aggressive treatment with surgical resection, radiation and chemotherapy, only 60% of children are cured of the tumor and most suffer life-long, devastating side effects including reduced intellect. The main problem with current treatments for MB is that they are not very specific for MB tumor cells. Thus, there is a critical need to develop new cancer therapies that selectively kill MB tumor cells.

Project Goal
In order to develop such therapies we need to know which genetic changes of MB are required for the survival of tumor cells. Unfortunately, the genetic changes involved in MB are poorly understood. In order to gain insight into the genes or pathways that are essential in MB, we are studying the proliferation of cerebellar granule cell precursors (GCPs), the cell type from which MB is thought to arise. We have recently determined that the number of GCPs in the developing cerebellum is reduced in mice that express low levels of the protein, MDM2. This discovery suggests that MDM2 may play an important role in the proliferation or survival of GCPs.

The goal of our research is to elucidate the function of MDM2 in cerebellar development and MB. Specifically, we will determine if MDM2 is required for the proliferation of GCPs. In addition, we will use mouse models of MB to test genetically whether MDM2 is required for the formation of MB. Together, these studies will contribute to our understanding of the signaling pathways important for GCP growth and proliferation, and will provide valuable insight into the utility of MDM2 as a therapeutic target for MB.