Dysregulation of the phosphoinositide 3-kinase (PI3-kinase) signaling pathway plays a key role in the development of glioma brain tumors. Novel agents that inhibit elements within the PI3-kinase pathway have entered clinical trials. The broad long-term objective of the proposed work is to utilize the molecular profile of individual tumors to guide therapy with effective, molecularly targeted treatments that will improve survival for glioma patients. To achieve this goal we must identify the most promising target for therapeutic inhibition, define the patient population likely to benefit from treatment with signaling inhibitors and validate the ability of molecular features to guide the choice of signaling inhibitor in the treatment of individual patients. To identify the signaling molecule whose inhibition is most likely to impact on patient survival, elements within the PI3-kinase cascade will be analyzed in diffuse gliomas of all grades. Molecules such as EGFR and PDGFR, that function upstream of PI3-1dnase, and molecules such as roTOR and PKB that function downstream of PI3-1dnase, will be characterized for each tumor and correlated with each other and with patient survival. In addition, we will define the subset of patients who are likely to benefit from inhibition of the PI3-kinase pathway. To validate the ability of molecular features to guide the choice of signaling inhibitor, we will analyze tumors from patients who are enrolled in currently open phase I clinical trials employing signaling inhibitors. The status of elements within the PI3-kinase pathway will be retrospectively correlated with tumor response to the novel agent. Furthermore, we propose a phase II trial in which we will prospectively examine the value of molecular profiling in selecting appropriate treatment for individual glioma patients. The choice of signaling inhibitor to be tested in this protocol will rest on the prevalence of the targeted aberration, the strength of its association with patient survival and any clinical response data that may arise from the completed phase I trials. In order to enhance the specificity of agents that inhibit the PI3-kinase pathway, we propose to incorporate into glioma therapy agents that target central elements of this signaling cascade. To this end we have developed approaches to specifically inhibit PI3-kinase or its immediate downstream effector PDK-1. The delivery and efficacy of these agents will be tested in xenograft models of human gliomas with the goal of incorporating them into the multimodality treatment of glioma patients.
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