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Targeting eEF2 Kinase in Neuroblastoma

University of California San Francisco
William Weiss, M.D., Ph.D.
Grant Type: 
Innovation Grants
Year Awarded: 
Type of Childhood Cancer: 
Project Description: 

To survive, cancer cells must adapt to stressful conditions. The generation of protein from an intermediate chemical called messenger RNA (a process dubbed translation) is the most energy demanding process in cells, explaining the myriad mechanisms to limit excess translation during stress. The master regulator of translational elongation, eukaryotic elongation factor 2 kinase (eEF2K), is activated during energy deprivation. This kinase was shown recently to confer resistance to energy deprivation (due to nutrient deprivation) in two different brain cancers. The one mechanism known for how this protein works, is that it activates a substrate called eE-F2, a master regulator that decides whether or not a cell should expend the energy required to generate proteins from messenger RNA. In analyzing public databases, we found that high expression of eEF2K correlated dramatically with poor outcome in neuroblastoma.

Project Goal
Our profiling of eEF2K revealed that this protein regulates the activity of proteins in addition to eE-F2, including those that control expression of MYCN, a protein that plays a major role in risk in neuroblastoma. We depleted eEF2K in neuroblastoma cells. This depletion drove neuroblastoma cells to die. We hypothesize that eEF2K is critical to survival in MYCN-dependent neuroblastoma, and that small molecule inhibitors will block tumor growth.  In this grant, we propose experiments to clarify the importance eEF2K as a target in neuroblastoma, to determine how modulation of eEF2K expression affects levels of MYCN, and to synthesize a small molecule that blocks eEF2K, that can be used as a prototype for therapy.