Research Project Summary: Ari Kane

Project Title: Local PI(3)-Kinase pathway inhibition to overcome glioma immunoresistance

The long-term goal of this project is to optimize immunotherapy for patients with malignant glioma. The short-term goal is to provide a superb training environment for the applicant to pursue a research plan within the realm of glioma immunology. Prognosis for malignant glioma has changed little over the past 25 years and side effects from systemic treatment remain undesirable. However, numerous studies have begun to reveal the underlying oncogenic processes including aberrant intracellular signaling, cell-surface protein expression, and immunosupression. My mentor’s laboratory has described signaling alterations in the PI(3)K pathway that lead to increased expression of B7-H1 on gliomas. B7-H1 confers tumor immunoresistance by inducing T-cell apoptosis. Recently several drugs have been developed that inhibit specific steps of the PI(3)K pathway. Building on these developments, our goal is to selectively disrupt oncogenic processes, improve tolerability and efficacy of therapy, and restore immune-mediated destruction of neoplastic tissue.  Using a rodent glioma implantation model, we will test the hypothesis that the local delivery of a PI(3)K pathway inhibitor using convection enhanced delivery is more effective and safe than systemic delivery. Furthermore, we will attempt to augment drug distribution in neoplastic tissue via liposomal encapsulation of the mTOR inhibitor CCI-779.  Lastly, we will assess the impact of combining biologically distinct therapies and evaluate the potentially synergistic effect of PI(3)K inhibition on response to adoptive immunotherapy.