Targeting the Hedgehog pathway in glioma tumor-initiating cells

靶向神经胶质瘤肿瘤起始细胞中的 Hedgehog 通路

• 批准号: 8397564
• 负责人: MICHAEL KANE COOPER
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8397564
• 关键词: Adjuvant Chemotherapy; Behavior; Biological; Biological Assay; Brain Neoplasms; Cell Proliferation; Cell Survival; Cells; Clinical; Collection; Data; Diagnosis; Disease; Erinaceidae; Excision; Foundations; GLI gene; Gene Targeting; Glioblastoma; Glioma; Goals; Growth; Hematologic Neoplasms; Human; Immunodeficient Mouse; Immunophenotyping; Individual; Infiltrative Growth; Investigation; Ligands; Malignant Glioma; Malignant Neoplasms; Measures; Modeling; Molecular; Molecular Target; Mus; Nature; Oligodendroglioma-Astrocytoma; Operative Surgical Procedures; PTCH gene; Pathway interactions; Patients; Phenotype; Pre-Clinical Model; Primary Brain Neoplasms; Primary Neoplasm; Radiation; Radiation therapy; Recurrence; Regulation; Research; Resistance; Sampling; Signal Transduction; Specimen; Surveys; Testing; Therapeutic; Therapeutic Intervention; Transplantation; United States; Veterans; Work; World Health Organization; Xenograft Model; Xenograft procedure; base; cancer stem cell; cell growth; cell type; chemotherapy; design; in vivo; innovation; mouse model; novel; outcome forecast; response; smoothened signaling pathway; statistics; tumor; tumor growth

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.

描述（由申请人提供）： 项目摘要恶性神经胶质瘤统称是大脑中最常见的原发性肿瘤，也是癌症的特别致命形式。神经胶质瘤的亚型根据世界卫生组织（WHO）建立的组织病理学和临床标准进行分类。谁的II-IV胶质瘤的特征是当前疗法的侵入性生长和顽固性，因此患有恶性神经胶质瘤的患者目前的预后较差。在异质性神经胶质瘤细胞类型中，CD133的表达已经鉴定出一种独特地赋予辐射和化学疗法的耐药性（Bao等，2006a; Liu等，2006）。从恶性神经胶质瘤中分离出的多能CD133+细胞具有在免疫缺陷小鼠中启动和完全概括疾病的能力（Singh等，2004）。脑肿瘤中肿瘤发射细胞类型的鉴定表明，像血液学恶性肿瘤一样，神经胶质瘤的异质细胞代表了分化状态的分层排列。根据这种范式，消除肿瘤发射细胞将提供最大的治疗益处。这一预测促使对调节肿瘤发射细胞的分子途径进行了广泛的研究。 刺猬（HH）途径是一种调节细胞分化的信号传导机制，其活性与其他恶性肿瘤的生长有关。我们在对患者样品的大规模调查中证明了HH途径在星形胶质细胞瘤和少突endrogliomas（II级II和III级）中，而不是在原发性胶质母细胞瘤Multonsoural（GBM; WHO IV级）中激活（Ehtesham等，2007年）。在III级胶质瘤中，我们发现HH途径成分PTCH和GLI1的表达分离为CD133+细胞。此外，我们已经测量了在具有直接原位异种移植物的III级神经胶质瘤的小鼠中对HH途径的药理抑制作用的显着生存优势，而不是来自原代GBM的HH途径。因此，我们假设CD133+细胞中的配体依赖性HH信号传导调节特定类型的恶性神经胶质瘤的生长。该提案的具体目的旨在在相关的临床前模型中严格检验该假设，并评估靶向恶性神经胶质瘤中HH途径的治疗效用。 该提案中的体内研究是在使用人神经胶质瘤手术标本和主要的异种移植小鼠模型中的创新性，以严格评估靶向既定恶性神经胶质瘤中HH途径的治疗效用。完成这项研究的目的将定义恶性神经胶质瘤的类型，因此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还将为优化靶向胶质瘤细胞的疗法提供基础，而这些疗法原本对当前疗法具有抗性。

项目成果

Identification of Hedgehog pathway responsive glioblastomas by isocitrate dehydrogenase mutation.

• DOI: 10.1016/j.canlet.2012.10.002
• 发表时间: 2013-01-28
• 期刊: CANCER LETTERS
• 影响因子: 9.7
• 作者: Valadez, J. Gerardo;Grover, Vandana K.;Carter, Melissa D.;Calcutt, M. Wade;Abiria, Sunday A.;Lundberg, Christopher J.;Williams, Thomas V.;Cooper, Michael K.
• 通讯作者: Cooper, Michael K.

Cancer stem cells in glioma: challenges and opportunities.

• DOI: 10.3978/j.issn.2218-676x.2013.08.01
• 发表时间: 2013-10-01
• 期刊: Translational cancer research
• 影响因子: 0.9
• 作者: Wang J;Ma Y;Cooper MK
• 通讯作者: Cooper MK

Expression of Hedgehog ligand and signal transduction components in mutually distinct isocitrate dehydrogenase mutant glioma cells supports a role for paracrine signaling.

Hedgehog 配体和信号转导成分在相互不同的异柠檬酸脱氢酶突变神经胶质瘤细胞中的表达支持旁分泌信号传导的作用。

• DOI: 10.1007/s11060-014-1481-7
• 发表时间: 2014
• 期刊: Journal of neuro-oncology
• 影响因子: 3.9
• 作者: Abiria,SundayA;Williams,ThomasV;Munden,AlexanderL;Grover,VandanaK;Wallace,Ato;Lundberg,ChristopherJ;Valadez,JGerardo;Cooper,MichaelK
• 通讯作者: Cooper,MichaelK