Notch in Neuroblastoma

神经母细胞瘤中的缺口

基本信息

批准号：
7991140
负责人：
Patrick A Zweidler-McKay
金额：
$ 20.62万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7991140
关键词：
Affect Biological Assay Brain Cell Line Cell Proliferation Cell model Cells Cessation of life Child Conflict (Psychology)Data Developmental Process Diagnosis Differentiation and Growth Disease Effectiveness Gene Expression Gene Targeting Genes Goals Growth Human In Vitro Knowledge Ligands Literature Malignant Childhood Neoplasm Measures Mediating Modeling Mus Neoplasm Metastasis Neural Crest Neurites Neuroblastoma Notch Signaling Pathway Operative Surgical Procedures Pathway interactions Patients Pattern Peptides Play Role Sampling Series Signal Transduction Solid Neoplasm Spinal Cord Staging Stem cells Testing Therapeutic Transplantation base cancer stem cell cell growth chemotherapy high risk in vivo notch protein novel novel therapeutic intervention public health relevance receptor relating to nervous system research study stem cell population tumor tumor growth tumor initiation

项目摘要

DESCRIPTION (provided by applicant): Neuroblastoma is the most common solid tumor in children outside of the brain and spinal cord. Half of affected patients have high risk disease at diagnosis and have <40% chance at cure despite aggressive chemotherapy, surgery and transplant, so new therapies are desperately needed. There is already evidence that the Notch pathway may play one or more roles in the growth and survival of neuroblastoma cells. However, it is not clear how uniform the effects of Notch signaling are, and whether Notch signaling plays an important role in neuroblastoma stem cells. Furthermore it is not known whether targeting the Notch pathway would be a promising therapeutic approach. Our preliminary data suggest that enhancing Notch signaling, and more specifically HES gene activity, leads to growth arrest and differentiation of neuroblastoma cell lines. We believe that Notch/HES signaling may inhibit neuroblastoma stem cell growth and survival, while limiting tumor-forming ability. Given this, our long-term goal is to develop Notch enhancing agents for the potential use in children with neuroblastoma. However, to achieve this goal we propose a series of experiments which will determine 1) whether it is likely that patient samples and a newly-described neuroblastoma stem cell population will respond to Notch signaling, 2) whether we can use a Notch-stimulating agents to induce growth arrest and differentiation in neuroblastoma cell lines and stem cells, and 3) whether stimulating Notch signaling in these cells can interfere with tumor growth and metastasis. In Aim 1 we will determine what the effects of enhancing and inhibiting the Notch/HES pathways are in neuroblastoma cell lines and stem cells. In Aim 2 we will test these findings in mice harboring human neuroblastoma tumors, measuring the effects of Notch signaling on tumor formation, growth, and differentiation. Here we will determine whether a Notch-enhancing peptide is effective and promising as a novel therapeutic approach. In Aim 3 we will examine the Notch/HES pathways using patient samples, a panel of cell lines and newly described neurosphere neuroblastoma stem cells. Through these experiments we will gain knowledge regarding the role(s) of Notch signaling in neuroblastoma stem cells, and will determine the effectiveness and feasibility of using a Notch-directed approach for the treatment of neuroblastoma. PUBLIC HEALTH RELEVANCE: Neuroblastoma is responsible for over 15% of all childhood cancer deaths and new therapies are needed. The Notch signaling pathway may play a role in neuroblastoma formation and/or growth through effects on neuroblastoma cancer stem cells. In this proposal, we will investigate this role with the long term goal of using Notch modulating agents as a novel treatment for neuroblastoma.

描述（由申请人提供）：神经母细胞瘤是儿童脑和脊髓以外最常见的实体瘤。一半受影响的患者在诊断时患有高风险疾病，尽管进行积极的化疗、手术和移植，治愈的机会仍低于 40%，因此迫切需要新的疗法。已有证据表明Notch通路可能在神经母细胞瘤细胞的生长和存活中发挥一种或多种作用。然而，目前尚不清楚Notch信号传导的影响有多一致，以及Notch信号传导是否在神经母细胞瘤干细胞中发挥重要作用。此外，尚不清楚靶向Notch通路是否是一种有前途的治疗方法。我们的初步数据表明，增强Notch信号传导，更具体地说是HES基因活性，会导致神经母细胞瘤细胞系的生长停滞和分化。我们认为Notch/HES信号传导可能抑制神经母细胞瘤干细胞的生长和存活，同时限制肿瘤形成能力。鉴于此，我们的长期目标是开发Notch增强剂，以用于患有神经母细胞瘤的儿童。然而，为了实现这一目标，我们提出了一系列实验，这些实验将确定 1) 患者样本和新描述的神经母细胞瘤干细胞群是否可能对 Notch 信号产生反应，2) 我们是否可以使用 Notch 刺激剂诱导神经母细胞瘤细胞系和干细胞的生长停滞和分化，以及3）刺激这些细胞中的Notch信号传导是否可以干扰肿瘤生长和转移。在目标 1 中，我们将确定增强和抑制 Notch/HES 通路对神经母细胞瘤细胞系和干细胞的影响。在目标 2 中，我们将在携带人类神经母细胞瘤肿瘤的小鼠中测试这些发现，测量 Notch 信号传导对肿瘤形成、生长和分化的影响。在这里，我们将确定Notch增强肽作为一种新的治疗方法是否有效且有前景。在目标 3 中，我们将使用患者样本、一组细胞系和新描述的神经球神经母细胞瘤干细胞检查 Notch/HES 通路。通过这些实验，我们将获得有关 Notch 信号在神经母细胞瘤干细胞中的作用的知识，并将确定使用 Notch 导向方法治疗神经母细胞瘤的有效性和可行性。公共卫生相关性：神经母细胞瘤占所有儿童癌症死亡人数的 15% 以上，因此需要新的疗法。 Notch 信号通路可能通过影响神经母细胞瘤癌症干细胞在神经母细胞瘤形成和/或生长中发挥作用。在本提案中，我们将研究这一作用，长期目标是使用 Notch 调节剂作为神经母细胞瘤的新型治疗方法。