The objective of this project is to understand the importance and regulation of autophagy and elongation factor-2 kinase (eEF-2 kinase) in glioblastoma multiforme (GBM), and to develop novel, autophagy targeted strategies for treatment of this most lethal primary brain tumor. Despite advances in the treatment of GBM, the prognosis of patients with this devastating disease remains poor. GBM is characterized by survival of glioma cells following initial treatment, invasion through the brain parenchyma and destruction of normal brain tissues, and ultimately resistance to current treatments. Recent evidence from several laboratories, including ours, suggest that autophagy, a conserved response to nutrient/growth factor deprivation and a process of self-digestion of cytoplasm and organelles through which cellular components are recycled for energy utilization, may represent a critical survival mechanism for cancer cells under various stress conditions. Furthermore, we found that eEF-2 kinase, a unique calmodulin- dependent enzyme that inhibits protein elongation and is overexpressed in glioma, is critically linked to activation of autophagy and protection of cell viability. Thus, autophagy might be a way that glioma cells subvert attempts at annihilation through stress-imposed hibernation. We hypothesize that glioma cells survive various stresses through activating an eEF-2 kinase-mediated autophagic survival pathway, and that inhibiting eEF-2 kinase will prevent the onset of autophagy, decrease GBM resilience, and hasten cell death via apoptosis. Therefore, we will investigate the causal and functional connection between activation of autophagy by eEF-2 kinase and resistance to apoptosis, and define the molecular events involved. We will determine whether the pro-survival role of the eEF-2 kinase-activated autophagy contributes to the malignant phenotypes such as migration and invasion (Aim 1). To understand the regulation of eEF-2 kinase activity in response to stress, we will study how various forms of stress affect the stability/activity of eEF-2 kinase, dissect the functions of phosphorylation of Ser366, Ser78 and Ser398 in regulating the ubiquitination and turnover of the kinase, and determine the roles and functional significance of the mTOR/S6 kinase and AMP kinase pathways in these regulatory processes (Aim 2). The impact of targeting eEF-2 kinase- mediated autophagic survival on GBM therapy will be tested in integrated studies with the human glioma cell lines and primary tumor-base, clinically relevant (invasive and CD133+) orthotopic glioma xenograft models developed by our collaborators at Baylor College of Medicine (Aim 3). Our initial studies have shown that NH125, the first potent and selective inhibitor of eEF-2 kinase that was discovered by our group and has been selected by the NCI's RAID program for further development, displayed a promising synergistic effect in combination treatment both in vitro and in vivo. The use of eEF-2kinase inhibitors in combination therapy for GBM is an attractive strategy that needs further investigation. The data gleaned from the proposed studies will not only shed significant new light on the poorly understood roles and implication of autophagy and eEF-2 kinase in GBM, but may also lead to identification of a new therapeutic target and to development of novel therapeutic interventions for patients with GBM.
This proposal is aimed at uncovering the importance and regulation of autophagy and the elongation factor-2 kinase (a.k.a. calmodulin-dependent protein kinase III) pathway in the pathogenesis of glioblastoma multiforme (GBM) and in its response to treatments. By elucidating the functional significance of the elongation factor-2 kinase-mediated autophagy in the survival of malignant glioma cells and tumor progression, it is our expectation that we will be able to design and develop novel and more effective therapeutic intervention for patients with this most lethal primary brain tumor. As eEF-2 kinase is overexpressed in malignant gliomas, targeting this kinase in combination with chemotherapy, radiotherapy, or other existing treatments to shuttle cells into more reliable and permanent pathways of cell death is an attractive therapeutic strategy that needs further investigation. This proposal is immediately relevant to the development of innovative therapeutic approaches against malignant brain tumors, and may ultimately have a large impact in improving GBM treatment.
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