PROTEASOMAL CONTROL OF GLIOBLASTOMA CANCER STEM CELL FUNCTION
Led by Albert Kim, MD PhD at Washington University School of Medicine
Proteasomes are large intracellular protein complexes designed to destroy proteins in a timely fashion. Proteasome inhibitor bortezomib has been tested in Phase I clinical trials in recurrent glioblastoma with evidence of some efficacy, and novel proteasome inhibitors with superior bloodbrain barrier penetration are becoming available. But to improve the effectiveness of proteasome-based therapies, a better understanding of how proteasome activity impacts glioblastoma biology is required. Glioblastoma cancer stem cells, a subpopulation of glioblastoma cells, are strikingly resistant to standard chemo- and radiation therapies, and even small numbers of glioblastoma stem cells can lead to the formation of invasive and aggressive tumors in animal models. We have found a critical role for proteasomes in the control of key glioblastoma stem cell functions, including stem cell identity and invasiveness, suggesting that manipulation of proteasomes might represent a glioblastoma stem cell-specific vulnerability. This proposal will take advantage of a unique resource of human patient-derived glioblastoma stem cells and employ molecular biology, protein biochemistry, in vivo, and cutting-edge proteomic approaches to (1) determine where precisely in the cell proteasomes regulate stem cell identity and invasiveness and (2) identify novel substrates of the proteasome that control glioblastoma
stem cell identity. The elucidation of proteasome-based molecular mechanisms in glioblastoma stem cell function will allow for the design of specific cancer stem cell-directed therapies, a strategic component of any effective treatment plan for glioblastoma multiforme.
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