Regulatory Mechanisms and Therapeutic Targeting of Brain Cancer "Stem Cells"

During the past decade, there has been a re-emergence of the concept that cancers harbor small populations of malignant stem-like cells (often referred to as cancer stem cells) that sustain tumor growth and recurrence. These neoplastic “stem cells” , which share the defining phenotypic characteristics of self-renewal, multipotential differentiation at least equivalent to that in the primary tumor, and long-term tumor propagation, have been identified in leukemia and multiple myeloma, and more recently in solid tumors including mammary carcinoma and primary brain tumors. The potential role for multipotent stem/progenitor cells in brain cancer initiation is supported by the fact that directing oncogenic growth signals to nestin- or GFAP-positive neural progenitor cells in rodents causes high grade glioma. Independent of the potential contribution of stem cells to tumor initiation, a current view is that neoplastic cells with stem-like properties underpin the maintanence and therapeutic resistance of malignant glioma. This concept is based on the identification of tumor cells that express stem cell markers (CD133, aldehyde dehydrogenase, sidepopulation), grow in vitro as neurospheres under serum-free conditions that support the growth of normal neural stem cells, resist ionizing radiation, and propagate tumor xenografts with high efficiency. An important feature of experimental tumor xenografts established from GBM-derived neurospheres enriched for neoplastic stem-like cells is they provide excellent experimental models that recapitulate the pathological features of actual glioblastoma (tumor cell invasiveness, necrosis, and vascular proliferation.

The overriding general hypothesis of this research collaborative is that neoplastic stem-like glioma cells play a critical role in the growth, invasiveness, and therapeutic resistance of malignant glioma. It follows that understanding the molecular mechanisms that regulate the tumorigenic phenotype of stem-like glioma cells will improve our understanding of malignant brain tumors and lead to novel stem cell-targeting therapeutics. Since considerable overlap exists between normal neurodevelopmental mechanisms and mechanisms that support neoplastic stem-like glioma cells, the effects of inhibitors of neoplastic “stem cells” on normal neurobiology must be considered.

Our application describes highly innovative collaborative research focusing on

1. understanding the molecular mechanisms that support the neoplastic stem-like phenotype
2. understanding the cellular and molecular mechanisms by which neoplastic stem-like cells invade brain
3. targeting oncogenic mechanisms in neoplastic stem-like cells
4. identifying clinically translatable biomarkers toward the goal of developing novel treatment strategies
5. testing the potential “toxicity” of targeted therapeutics on normal neurobiological processes.