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）： 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。

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