The Notch signaling pathway in glioblastoma

胶质母细胞瘤中的Notch信号通路

• 批准号: 8126802
• 负责人: Anthony C Wang
• 金额: $ 5.3万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8126802
• 关键词: Achievement; Address; Adult; Age; Apoptosis; Area; Basic Science; Brain; Brain Neoplasms; Cancer Biology; Cancerous; Cell Differentiation process; Cell Proliferation; Cell Survival; Cells; Cellular biology; Clinical; Clinical Trials; Data; Dexamethasone; Diffuse; Disease; Engraftment; Glioblastoma; Goals; Growth; Growth Inhibitors; Human; Human Development; Immunocompromised Host; In Vitro; Incidence; Infiltration; Intestines; Laboratory Research; Magnetic Resonance Imaging; Malignant Glioma; Malignant Neoplasms; Malignant neoplasm of brain; Mediator of activation protein; Modality; Modeling; Molecular; Monitor; Mus; Neuraxis; Neurosurgeon; Notch Signaling Pathway; Nude Mice; Oncologist; Operative Surgical Procedures; Pathway interactions; Patients; Pattern; Play; Population; Positioning Attribute; Proliferating; Property; Radiation; Radiation therapy; Recurrence; Regimen; Regulation; Resistance; Role; Sampling; Scientist; Series; Side; Solid Neoplasm; Stem cells; Stomach; Study models; System; Testing; Therapeutic; Toxic effect; Translating; Translations; Tumor Volume; Work; Xenograft Model; Xenograft procedure; base; cancer stem cell; cell growth; chemotherapeutic agent; design; gamma secretase; improved; in vivo; inhibitor/antagonist; medulloblastoma; mouse model; neoplastic cell; nerve stem cell; notch protein; novel; novel therapeutics; research study; stem; stem cell biology; stem cell differentiation; success; temozolomide; theories; tumor; tumor growth

DESCRIPTION (provided by applicant): Glioblastoma multiforme (GBM) is the most common malignant brain tumor in adults. Less than 5% of patients survive more than 2 years and new therapeutic strategies are desperately needed. The Notch signaling pathway plays a crucial role in regulation of multi-potent stem cells in the development of the human central nervous system. In addition, it has been shown that GBMs contain a sub-population of cancer stem-like cells (CSLCs) that demonstrate elevated Notch activity. However, it is as yet unknown whether Notch pathway blockade could target CSLCs in GBM. Recent studies have shown that primary cultures of GBM propagating as neurospheres more accurately replicate the infiltrating growth patterns seen in the native brain tumor, and contain CSLCs with stem-like multi-potent capacity. Among solid tumors, brain CSLCs are by far the mostly well-studied. This is due, at least in part, to the well-developed neurosphere culture systems. We have obtained four GBM neurosphere lines from Dr. Angelo Vescovi. Other GBM models we study include several lines of primary patient-derived GBMs engrafted intracranially in immunocompromised mice obtained from Dr. Sean Morrison, as well as three primary low-passage GBM cultures. We are, therefore, well positioned to further address this exciting new area of cancer biology. In the current application, we propose a series of studies using these models, focusing on targeting GBM CSLCs by Notch pathway inhibition (gamma secretase inhibitor-18), both in vitro and in vivo. We will also design a realistic combination therapeutic regimen to facilitate its clinical translation. Specific Aim #1 is to determine effects of Notch pathway inhibition on CSLCs in primary GBMs in vitro and in vivo. Specific Aim #2 is to examine the effects of Notch inhibition in combination with Akt inhibition or common chemo-radiation therapies on GBM CSLC-derived mouse tumor model. Success in the current proposal will not only enhance our understanding CSLC biology in general, but also has the potential for direct translational impact on GBM treatment in our patients. PUBLIC HEALTH RELEVANCE: Glioblastoma is the most malignant brain tumor in adult with no successful treatment during the past thirty years. The goal of this proposal is to understand how an important molecular pathway known as Notch regulates glioblastoma initiating cells, develop a novel therapeutic strategy, and eventually translate the laboratory research into a clinical trial through a team work among the top-notch basic research scientists, Oncologists, and neurosurgeons.

描述（由申请人提供）：多形胶质母细胞瘤（GBM）是成人最常见的恶性脑肿瘤。不到5％的患者生存了2年以上，迫切需要新的治疗策略。 Notch信号通路在人类中枢神经系统的发展中调节多功能干细胞的调节中起着至关重要的作用。此外，已经表明，GBM含有癌症干细胞（CSLC）的亚群，这些细胞表现出较高的凹口活性。但是，尚不清楚Notch途径封锁是否可以针对GBM中的CSLC。 最近的研究表明，GBM的主要培养物作为神经球更准确地复制了在天然脑肿瘤中看到的浸润生长模式，并包含具有类似茎样的多力量能力的CSLC。在实体瘤中，脑CSLC是迄今为止大多数研究的。这至少部分归因于发达的神经圈培养系统。我们从Angelo Vescovi博士那里获得了四个GBM神经球线。我们研究的其他GBM模型包括几条原发性患者衍生的GBM，颅内植入了从Sean Morrison博士获得的免疫功能低下的小鼠中，以及三种原发性低通量GBM培养物。因此，我们有好处，可以进一步解决这个令人兴奋的癌症生物学领域。 在当前的应用中，我们提出了一系列使用这些模型的研究，并通过Notch途径抑制（Gamma secralse抑制剂-18）靶向GBM CSLC，包括体外和体内。我们还将设计一种现实的组合治疗方案，以促进其临床翻译。具体目的＃1是确定Notch途径抑制对原代GBMS中CSLC的影响。具体目的＃2是检查Notch抑制作用与AKT抑制作用或常见化学辐射疗法对GBM CSLC衍生的小鼠肿瘤模型的影响。当前建议中的成功不仅会增强我们的理解CSLC生物学，而且还具有直接转化对患者GBM治疗的可能性。 公共卫生相关性：胶质母细胞瘤是成人中最恶性的脑肿瘤，在过去的三十年中没有成功治疗。该提案的目的是了解一种称为Notch的重要分子途径如何调节胶质母细胞瘤启动细胞，制定新的治疗策略，并最终通过顶尖的基础研究科学家，肿瘤学家，肿瘤学家和Neurosurgeons之间的团队工作将实验室研究转化为临床试验。