Presentation Abstract

Abstract Number: 3318
Presentation Title: Molecular targeting of brain tumor stem cells
Presentation Time: Tuesday, Apr 20, 2010, 9:00 AM -12:00 PM
Location: Exhibit Hall A-C, Poster Section 15
Poster Section: 15
Poster Board Number: 5
Author Block: Christine E. Eyler1, Michael T. Forrester1, Jennifer M. MacSwords2, Qiulian Wu2, Katherine M. LaFiura1, Justin D. Lathia2, Andrew E. Sloan3, Jeongwu Lee2, Roger E. McLendon1, Anita B. Hjelmeland2, Jeremy N. Rich2. 1Duke University, Durham, NC; 2Cleveland Clinic, Cleveland, OH; 3University Hospital-Case Medical Center and Case Western School of Medicine, Cleveland, OH
Abstract Body: Although current therapeutic strategies for malignant gliomas are non-specifically directed against the tumor bulk, increasing evidence suggests that a single glioma contains a range of phenotypically disparate cell populations with differential capacity for tumor maintenance and initiation. Recent work in brain tumors suggests the existence of cellular sub-populations (known as cancer stem cells, or CSCs) that possess stem cell-like behaviors and a potent capacity for tumor initiation in transplantation assays relative to non-CSCs. Specifically targeting the highly tumorigenic CSCs has the potential to improve the prognosis of malignant glioma patients, but many molecularly-directed anti-CSC agents may also compromise the survival of normal neural stem cells due to molecular similarities between CSCs and normal stem cells. Here we demonstrate that malignant glioma CSCs express high levels of a particular protein relative to non-CSCs. Glioma CSC growth and tumorigenic capacity were abrogated by multiple strategies interfering with the expression and activity of this protein, including RNA interference, pharmacological inhibition, and heterologous expression of a prokaryotic enzyme that specifically consumes the enzymatic product of this critical protein. Importantly, tumor growth was inhibited by systemic treatment of xenograft-bearing mice with a well-studied small molecule inhibitor of this protein that has already demonstrated low toxicity in clinical trials for other diseases. Though the activity of this protein appears critical for the maintenance of highly tumorigenic glioma CSCs, our examination of both normal human neural progenitor cells and neural stem cells derived from genetically disrupted mice indicate no substantial role for this protein in normal neural stem cells. Our findings identify a novel glioma therapeutic target with a negligible role in normal neural stem cells, suggesting clinical utility for selective inhibitors of this CSC-specific molecular target.