Targeting the Hedgehog pathway in glioma tumor-initiating cells

描述（由申请人提供）： 恶性神经胶质瘤是最常见的原发性脑肿瘤，是一种特别致命的癌症。胶质瘤的亚型是根据世界卫生组织（WHO）建立的组织病理学和临床标准进行分类的。WHO II-IV级神经胶质瘤的特征在于侵袭性生长和对当前疗法的耐受性，因此患有恶性神经胶质瘤的患者目前具有非常差的预后。在异质性神经胶质瘤细胞类型中，已经通过CD 133的表达鉴定出一种独特地赋予对放射和化学疗法的抗性的细胞类型（Bao et al.，2006 a; Liu等人，2006年）。从恶性胶质瘤分离的多能CD 133+细胞具有在免疫缺陷小鼠中引发和完全重现疾病的能力（Singh等人，2004年）。脑肿瘤中肿瘤起始细胞类型的鉴定表明，与血液恶性肿瘤一样，神经胶质瘤的异质细胞代表分化状态的分级排列。根据这种模式，消除肿瘤起始细胞将提供最大的治疗益处。这一预测促进了对调节肿瘤起始细胞的分子途径的广泛研究。 Hedgehog（Hh）通路是调节细胞分化的一种信号传导机制，其活性与其他恶性肿瘤的生长有关。我们已经在对患者样本的大规模调查中证明，Hh途径在星形细胞瘤和少突胶质细胞瘤（WHO II级和III级）中是可操作的和活化的，而在原发性多形性胶质母细胞瘤（GBM; WHO IV级）中不是（Ehtesham等人，2007年）。在III级胶质瘤中，我们发现Hh通路组分PTCH和GLI 1的表达分离到CD 133+细胞。此外，我们已经测量了一个显着的生存优势与药理学抑制Hh通路的小鼠轴承直接原位异种移植从III级胶质瘤，但不是从一个主要的GBM。因此，我们推测，配体依赖性Hh信号在CD 133+细胞调节特定类型的恶性胶质瘤的生长。该提案的具体目的是在相关的临床前模型中严格检验这一假设，并评估靶向Hh通路在恶性胶质瘤中的治疗效用。 该提案中的体内研究在使用人脑胶质瘤手术标本和原发性异种移植小鼠模型以严格评估靶向Hh通路在已建立的恶性胶质瘤中的治疗效用方面具有创新性。完成这项研究的目的将确定恶性胶质瘤的类型，从而确定可能对新型靶向分子治疗产生反应的患者。从这些研究中获得的信息也将为优化治疗提供基础，以靶向对当前治疗具有耐药性的胶质瘤细胞。 公共卫生相关性： 在美国，每年大约有15，750人被诊断患有恶性胶质瘤，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神经胶质瘤特别致命的性质。恶性神经胶质瘤是最常见的原发性脑肿瘤，目前的治疗方法尚不成熟。放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。迫切需要更有效的治疗干预措施。本提案中的研究涉及特异性靶向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学疗法的抗性。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.