Astrocytoma is the most common maligant brain tumor in humans and is currently incurable due to its diffusely infiltrative behavior. We have developed a mouse model of astrocytoma that recapitulates the infiltrative behavior of human astrocytoma. In this mouse model the tumor suppressor genes Nf1 and p53 are mutated. With the recent identification of mutations in NF1 in sporadic glioblastoma (GBM), this mouse model is a powerful tool for understanding the biology of tumors associated with neurofibromatosis type 1, as well as sporadic anaplastic astrocytomas and glioblastomas. We are using this mouse model to examine the signal transduction pathways necessary for proliferation and migration of astrocytoma cells both in vivo and in vitro. An understanding of these mechanisms will lead to the development of new therapies for astrocytoma. During fiscal year 2009, we have examined the efficacy of inhibitors of the PI3k/AKT/mTOR pathway on inhibition of astrocytoma proliferation. We are also studying several proteins important in neural stem cell fate and neural development in tumor cell biology. We have identified specific phosphorylation sites in one of these proteins that respond to growth inducing signals and changes the chromatin binding affinity of the protein. We are currently working to understand the biological significance of the signal induced change in these phosphorylation sites. In parallel with our cell line experiments, we have generated genetically engineered mouse models for our genes of interest to study them in vivo in the upcoming years.
