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Molecular Mechanisms of Tumor-Propagation by Human Glioblastoma Stem Cells

Glioblastoma multiforme (GBM) is the most common and most aggressive brain cancer. Survival for patients with GBM remains dismal. Half of the patients survival for less than 14 months and few live beyond 5 years. Understanding how GBM resists our most aggressive surgery, radiation, and chemotherapies is critical to improving patient care, quality of life and survival. 

Recent findings have found that a small subset of cancer cells within human GBM have the features of cancer stem cells. When these cells grow, they are able to replace themselves and generate more differentiated cancer cells. If implanted to rodent brain, these cancer stem cells are capable of forming aggressive tumors that mimic real human GBM. When placed under special conditions in the laboratory, these cells can also “differentiate” to resemble specific neuronal cell types (e.g. astrocytes, neurons). It is currently believed that GBM stem cells (GBM-SCs) are required to maintain GBM growth and it is possible that a single surviving GBM-SC can cause the cancer to recur. These findings predict that curing glioblastoma will require therapy that either kills the malignant stem- cells or permanently prevents tham from growing. Since GBM-SCs are relatively resistant to current therapies, identifying the molecular processes that allow them to form tumors is needed to target and treat the GBM-SCs effectively. 

We have recently found that the ability of GBM-SCs to grow in the laboratory and generate tumors in experimental animals is blocked by a class of chemicals called histone deacetylase inhibitors (HDACIs). HDACIs alter cellular gene expression. We have identified a number of genes and their protein products that are affected by HDACIs in GBM-SCs. Two of these genes are particularly novel and exciting within the context of GBM and cancer stem cell biology. We have already found that one of these genes, called DNER, can directly block the ability of GBM-SCs to grow in the laboratory and form tumors in animals. We now plan to determine how HDACIs, DNER, and a second promising HDACI-responsive gene, ID4, alter human GBM-SC growth and tumor formation. Our research will involve the production of multiple new GBM-SCs from consenting Johns Hopkins Hospital neurosurgery patients. These cells will become a valuable resource for other Maryland scientists interested in studying GBM-SCs. Our successful results will identify how GBM-SC grow and maintain themselves, identify new ways to target GBM-SC and thereby treat patients with GBM.