This grant proposes to compare and contrast genetically engineered mouse models of gliomas and medulloblastomas to investigate the stem-like cells of the perivascular niches (PVN) in these tumors. We will investigate what signaling pathways cells of the PVN use to respond to standard therapy used for humans. The Akt, nitric oxide, sonic hedgehog, and notch pathways are all active in these cells. Our preliminary data indicates that both temazolamide and radiation activate some of these pathways with resultant enhancement of stem cell character for cells occupying the PVN. Increased stem cell character is associated with resistance to both radiation and chemotherapy by multiple mechanisms. One goal is to determine the causal relationship between these pathways as a part of therapeutic response. Multi-drug resistance in these tumors is primarily due to activity of ABCG2 (a CNS stem cell marker), and is linked to the resistance of these tumors to chemotherapy. ABCG2 function is enhanced as a response to therapy as well. This fact has a substantial impact on the standard of care for gliomas (temazolamide with concurrent radiation) as both temazolamide and radiation induce ABCG2 and temazolamide is a substrate for ABCG2. Our additional goal is therefore to link the activation of ABCG2 to therapy through signaling pathways that could be blocked by available small molecule inhibitors. Eventually we hope to create a rational cocktail of therapy that would minimize the enhancement of stem cell character and multi-drug resistance in cells of the perivascular niche in gliomas and medulloblastomas.
Brain tumors are devastating forms of cancer. In adults the most common type of brain tumors are gliomas, the most common of which are essentially 100% fatal with survivals of 1 year. The most common type of solid cancer in children is the brain tumors called medulloblastomas. Although a higher percent of medulloblastoma patients are cured by current treatments than are glioma patients, the medulloblastoma patients are substantially injured by the treatments. This grant proposes to use mouse models medulloblastomas and gliomas to understand the biology of stem cells in these tumors and their response to therapy.
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