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. Because both NF1 and p53 are frequently mutated 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 2011, we continued our focus on three main pathways. In the first, we have examined the efficacy of inhibitors of the PI3k/AKT/mTOR pathway on inhibition of astrocytoma proliferation. Through the study of this pathway we are beginning to look at the different roles of AKT1, 2, and 3 in human and mouse brain tumors, and the relative roles of the mTORC1 and mTORC2 complexes. Our initial characterization of the EGFR/PI3K/AKT/mTOR signaling pathway in the Nf1/p53 mouse model was published in Neuro-Oncology in 2011. A second pathway that was elucidated during fiscal year 2010 was the phosphorylation of the chromatin modulator, BMI1, by an EGFR/CK2/PP1 signaling pathway independent of the PI3K/AKT pathway. We have identified specific phosphorylation sites in BMI1 that respond to EGFR signaling and changes the chromatin binding affinity of BMI1. During this fiscal year we demonstrated that this signaling pathway is critical for tumor growth in vitro and in vivo, and for neural stem cell maintenance. These data have been recently submitted for publication. Finally, we have begun work on a third signaling pathway involving cAMP and PKA in both astrocytoma cells and MPNST cells, in collaboration with Joshua Rubins group at Washington University. We have found that tumor cell contain increased levels of cAMP and PKA activity, in contrast to expectations from previous results. We are currently working to understand the implications of these finding and to study them further, particularly since they have implications for clinical trials with molecularly targeted agents for this pathway.
