Novel Molecular Mechanism of Glioma Pathogenesis

描述（申请人提供）：恶性胶质瘤是最常见的原发性脑肿瘤亚型，具有侵袭性和神经破坏性。多形性胶质母细胞瘤（GBM）是最常见的胶质瘤形式，其患者的平均生存时间约为1年，迄今尚无有效的治疗方法。关于GBM肿瘤发生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。我们了解癌症干细胞的关键问题之一是确定驱动癌症干细胞发育和自我更新的分子电路。基于我们最近的实验结果，我们提出评估FoxM1的新假设，FoxM1在人类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”细胞的高自我更新率，从而促进致瘤性。本研究拟探讨FoxM1与p53抑癌基因在神经干细胞肿瘤发生中的作用；FoxM1在维持胶质瘤干细胞特性中的重要作用。如果完成了本次资助申请的Specific Aims，我们不仅可以通过FoxM1表达异常维持GBM源性癌症“干细胞”自我更新来了解GBM分子癌发生的新机制，还可以了解FoxM1是否可以作为潜在的治疗靶点。这些信息将具有潜在的高翻译影响。从长远来看，我们的研究可能会导致分子靶点的验证，这些靶点可用于设计有效的策略，以在临床上控制这种致命疾病。

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.