PI: Fausto J. Rodriguez M.D., Johns Hopkins Medical Institute
new 2011-2012, one-year
Patients with pilocytic astrocytoma (PA) generally have favorable outcomes following surgical intervention, although a subset may cause significant morbidity or mortality, despite lack of atypical histologic features. Unlike diffuse gliomas, increased proliferation, invasive growth pattern, and/or necrosis do not always predict aggressive behavior in PA, although we have previously shown that frank anaplastic histologic change in the form of brisk mitotic activity with or without necrosis may portend a worse survival. Insight into the molecular alterations and pathways underlying aggressive behavior in pediatric low grade gliomas is needed, to decrease the morbidity and mortality associated with these tumors and conventional therapies. The importance of the PI3K/AKT/mTOR signaling axis has been highlighted in diffuse and high grade gliomas, and there is increasing interest in pharmacological targeting of this pathway in the pediatric setting, given recent successes reported with some low grade gliomas such as subependymal giant cell astrocytoma. However, little is known about the role of AKT/mTOR signaling in PA, the most common primary glioma in children. Some studies have highlighted a role for mTOR activation in NF1-associated PA, and we have also reported preliminary data suggesting that it mediates phenotypic variations in NF1-associated low grade gliomas with unusual morphologies. In addition, we have recently documented an association with phospho-AKT (ser473) and specific aggressive PA subtypes, but its clinical significance, in particular relationship to outcome, remains to be tested in a formal manner to justify specific therapeutic approaches. The goal of this proposal is to examine the role of PI3K/AKT/mTOR signaling in PA to determine if therapies targeting this pathway should be tested in children.
We are grateful to the CBTF and Tennis for Tumors for their kind support of this grant.