Novel Molecular Mechanism of Glioma Pathogenesis

描述(申请人提供)：恶性胶质瘤，最常见的原发脑肿瘤亚型，具有侵袭性和神经破坏性。多形性胶质母细胞瘤(GBM)是最常见的胶质瘤，其患者的平均生存期约为1年，目前尚无有效的治疗方法。目前对GBM致癌的分子机制知之甚少。人GBM的恶性表型可能是由GBM来源的干细胞(GSCs)驱动的。我们理解癌症干细胞的关键问题之一是确定驱动癌症干细胞发展和自我更新的分子电路。基于我们最近的实验结果，我们建议评估一种新的假设，即FOXM1在人GBM来源的干细胞(GSCs)中异常表达，可能通过PDGF-A介导的机制，导致肿瘤中存在的“干细胞”具有高的自我更新率，从而促进肿瘤的发生。在这里，我们建议评估FOXM1与p53肿瘤抑制基因在神经干细胞致癌中的协同作用，以及FOXM1在维持胶质瘤干细胞特性方面的重要作用。如果此次拨款申请的具体目标完成，我们不仅将了解通过FOXM1表达异常维持GBM来源的癌症干细胞自我更新的GBM分子肿瘤发生的新机制，而且我们还将了解FOXM1是否可以作为潜在的治疗靶点。这些信息可能会对翻译产生很大的影响。从长远来看，我们的研究可能会导致分子靶标的验证，这些靶标可以用于设计有效的策略，在临床上控制这种致命的疾病。 公共卫生相关性：多形性胶质母细胞瘤(GBM)是最常见的胶质瘤，其患者的平均生存期约为1年，到目前为止还没有有效的治疗方法。如果这项拨款申请的具体目标完成，我们不仅将了解通过FOXM1异常维持GBM来源的癌症干细胞自我更新而导致GBM肿瘤发生的新机制，而且我们还将了解FOXM1或其靶点PDGF-A是否可以作为潜在的治疗靶点。此信息将具有潜在的翻译影响。从长远来看，我们的研究可能导致分子靶标的确定，这些分子靶标可以用于设计有效的策略来控制这种致命的疾病。

DESCRIPTION (provided by applicant): Malignant glioma, the most common primary brain tumor subtype, is aggressive and neurologically destructive. The mean survival duration of patients with glioblastoma multiforme (GBM), the most common form of glioma, is approximately 1 year and there is no effective therapy to date. Little is known about the molecular mechanisms underlying GBM oncogenesis. The malignant phenotype of human GBM may be driven by GBM-derived stem-like cells (GSCs). One of the key issues for our understanding of cancer stem cells is to define the molecular circuitry that drives the development and self-renewal of the cancer stem cells. Based on our recent experimental results, we propose to evaluate the novel hypothesis that FoxM1, which is abnormally expressed in human GBM-derived stem-like cells (GSCs), causes a high self-renewal rate in the "stem-like" cells present in the tumor, possibly through a PDGF-A-mediated mechanism, and, thus contribute to tumorigenicity. Here, we propose to evaluate the oncogenic function of FoxM1 in cooperation with p53 tumor suppressor gene in oncogenesis of neural stem cells; and the essential role of FoxM1 in maintaining the characteristics of glioma stem-like cells. If the Specific Aims of this grant application are completed, not only will we understand a new mechanism of GBM molecular oncogenesis through abnormal maintenance of GBM-derived cancer "stem" cell self-renewal via FoxM1 expression, but also will we learn whether FoxM1 can serve as potential therapeutic targets. This information will have potentially high translational impact. In the long term, our study may lead to the validation of molecular targets that can be used in designing effective strategies to control this deadly disease in clinics. PUBLIC HEALTH RELEVANCE: The mean survival duration of patients with glioblastoma multiforme (GBM), the most common form of glioma, is approximately 1 year and there is no effective therapy to date. If the Specific Aims of this grant application are completed, not only will we understand a new mechanism of GBM tumorigenesis through abnormal maintenance of GBM-derived cancer "stem" cell self-renewal via FoxM1, but we will also learn whether FoxM1 or its target PDGF-A can function as potential therapeutic targets. This information will have potential translational impact. In the long term, our study may lead to the identification of molecular targets that can be used in designing effective strategies to control this deadly disease.