Targeting the Hedgehog pathway in glioma tumor-initiating cells

描述(由申请人提供)： 恶性胶质瘤是最常见的脑部原发肿瘤，也是一种特别致命的癌症。根据世界卫生组织(WHO)制定的组织病理学和临床标准对胶质瘤的亚型进行分类。世卫组织II-IV级胶质瘤的特点是侵袭性生长和对当前治疗的顽固性，因此目前恶性胶质瘤患者的预后非常差。在不同的胶质瘤细胞类型中，CD133的表达已被鉴定为具有独特的放射和化疗抗性(Bao等人，2006a；Liu等人，2006)。从恶性胶质瘤分离的多潜能CD133+细胞能够在免疫缺陷小鼠中启动和完全概括疾病(Singh等人，2004年)。脑肿瘤中肿瘤起始细胞类型的鉴定表明，与血液系统恶性肿瘤一样，胶质瘤的异质细胞代表了分化状态的分级排列。根据这一范例，消除启动肿瘤的细胞将提供最大的治疗益处。这一预测促使人们对调节肿瘤启动细胞的分子途径进行了广泛的研究。Hedgehog(HH)通路是调节细胞分化的一种信号机制，其活性与其他恶性肿瘤的生长有关。我们在对患者样本的大量调查中证明，HH通路在星形细胞瘤和少突胶质细胞瘤(WHO II级和III级)中可操作和激活，而在原发多形性胶质母细胞瘤(GBM；WHO IV级)中不起作用(Ehtesham等人，2007年)。在III级胶质瘤中，我们发现HH通路组件PTCH和GLI1的表达分离到CD133+细胞。此外，我们测量了在药物抑制HH途径的情况下，携带来自III级胶质瘤而不是来自原发基底膜的直接原位异种移植的小鼠的显著生存优势。因此，我们假设CD133+细胞中的配体依赖的HH信号调节特定类型恶性胶质瘤的生长。这项建议的具体目的是在相关的临床前模型中严格测试这一假说，并评估靶向HH通路在恶性胶质瘤中的治疗作用。这项建议中的体内研究在使用人脑胶质瘤手术标本和原始异种小鼠模型方面具有创新性，以严格评估靶向HH途径在已建立的恶性胶质瘤中的治疗效用。完成这项研究的目标将确定恶性胶质瘤的类型，从而确定可能对新的靶向分子疗法有反应的患者。从这些研究中获得的信息也将为优化针对胶质瘤细胞的治疗提供基础，否则这些细胞对当前的治疗方法具有抵抗力。 公共卫生相关性： 项目简介在美国，每年约有15,750人被诊断出患有恶性胶质瘤，估计有12,740名患者死于这种疾病。这些统计数据突出了恶性胶质瘤的特别致命性。恶性胶质瘤是最常见的脑部原发肿瘤，对目前的治疗方法难以抗拒。放射治疗和辅助化疗可适度延长生存期，手术切除对生存期的影响仍不明确。有必要采取更有效的治疗干预措施。这项建议中的研究涉及一种专门针对胶质瘤细胞类型的策略，这些细胞类型独特地赋予对放射和化疗的抵抗力。这项工作的目标是为退伍军人和其他恶性胶质瘤患者提供一种新的治疗方法。

DESCRIPTION (provided by applicant): PROJECT SUMMARY Malignant gliomas collectively represent the most common primary tumors of the brain, and a particularly lethal form of cancer. The subtypes of glioma are classified according to histopathological and clinical criteria established by the World Health Organization (WHO). WHO grades II-IV gliomas are characterized by invasive growth and recalcitrance to current therapies, and thus patients with malignant gliomas currently have a very poor prognosis. Among the heterogeneous glioma cell types, one that uniquely confers resistance to radiation and chemotherapy has been identified by the expression of CD133 (Bao et al., 2006a; Liu et al., 2006). Multipotent CD133+ cells isolated from malignant glioma have the capacity to initiate and fully recapitulate disease in immunodeficient mice (Singh et al., 2004). The identification of a tumor-initiating cell type in brain tumors suggests that, like hematological malignancies, the heterogeneous cells of gliomas represent a hierarchical arrangement of differentiation states. According to this paradigm, elimination of tumor-initiating cells would provide the greatest therapeutic benefit. This prediction has prompted extensive investigation of molecular pathways that regulate tumor-initiating cells. The Hedgehog (Hh) pathway is one signaling mechanism that regulates cellular differentiation, and whose activity has been implicated in the growth of other malignancies. We have demonstrated in a large survey of patient samples that the Hh pathway is operational and activated in astrocytomas and oligodendrogliomas (WHO grades II and III) and not in primary glioblastoma multiforme (GBM; WHO grade IV) (Ehtesham et al., 2007). Within grade III gliomas, we find that expression of the Hh pathway components PTCH and GLI1 segregate to CD133+ cells. Furthermore, we have measured a significant survival advantage with pharmacological inhibition of the Hh pathway in mice bearing direct orthotopic xenografts from grade III gliomas but not from a primary GBM. We therefore hypothesize that ligand-dependant Hh signaling in CD133+ cells regulates the growth of specific types of malignant glioma. The specific aims of this proposal have been designed to rigorously test this hypothesis in a relevant preclinical model and assess the therapeutic utility of targeting the Hh pathway in malignant glioma. The in vivo studies in this proposal are innovative in the use of human glioma surgical specimens and a primary xenograft mouse model to rigorously assess the therapeutic utility of targeting the Hh pathway in established malignant gliomas. Accomplishing the aims of this study will define the types of malignant glioma and thus patients that might respond to a novel targeted molecular therapy. Information gained from these studies will also provide the foundation for optimizing therapies to target glioma cells that are otherwise resistant to current therapies. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE Every year in the United States, approximately 15,750 individuals are diagnosed with a malignant glioma and an estimated 12,740 patients succumb to this disease. These statistics highlight the particularly lethal nature of malignant gliomas. Malignant gliomas represent the most common primary tumors of the brain, and are recalcitrant to current therapies. Radiotherapy and adjuvant chemotherapy prolong survival by a modest extent and the impact of surgical resection on survival remains poorly defined. There is an important need for more effective therapeutic interventions. The studies in this proposal pertain to a strategy for specifically targeting glioma cell types that uniquely confer resistance to radiation and chemotherapy. The goal of this work is to provide a novel therapy for Veterans and other patients with malignant gliomas.