TMEM108 IS A NOVEL TARGET IN NEUROBLASTOMA

TMEM108 是神经母细胞瘤的新靶点

• 批准号: 9276802
• 负责人: JIANHUA YANG
• 金额: $ 23.78万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9276802
• 关键词: Adult; Alpha Cell; Antibodies; Apoptosis; Binding; C-terminal; Cancer Cell Growth Regulation; Cell Culture Techniques; Cell Line; Cell Proliferation; Cell Surface Receptors; Cessation of life; Child; Data Set; Defect; Disease; Disease Outcome; Dose; Extracellular Domain; Future; Genes; Goals; Growth; In Vitro; Integral Membrane Protein; Knock-out; Length; MYCN gene; Malignant - descriptor; Malignant Childhood Neoplasm; Malignant Neoplasms; Mediating; Mediator of activation protein; Molecular Target; Monoclonal Antibodies; Mus; N-terminal; Neuroblastoma; Oncogenic; Oryctolagus cuniculus; Patient-Focused Outcomes; Patients; Peptide Signal Sequences; Play; Protein Secretion; Proteins; Recurrence; Regimen; Regulation; Research Proposals; Role; Sampling; Signal Pathway; Signal Transduction; Solid Neoplasm; Somatic Mutation; Testing; Therapeutic; Tumor Cell Line; Work; Xenograft procedure; angiogenesis; base; cell motility; chemotherapeutic agent; experimental study; in vivo; knock-down; mouse model; mutant; neuroblastoma cell; novel; overexpression; polyclonal antibody; therapeutic target; tumor; tumor growth; tumorigenesis; vector control

Neuroblastoma (NB) is the most common extracranial malignant solid tumor in children and contributes to more than 15% of all pediatric cancer-related deaths. Despite the overall improvement in the disease outcome, MYCN-amplified (MYCNA) NB largely remains an incurable disease. Unlike in adult tumors, recurrent somatic mutations in NB occur with relative paucity. Therefore, de-regulation of oncogenic signal transduction may contribute to NB tumorigenesis. This proposal will pursue that goal by defining the role and regulation of transmembrane protein 108 (TMEM108) in NB malignancy and examining the effect of TMEM108 inhibition on NB cell proliferation and tumor growth in an orthotopic mouse model. TMEM108 is a potential cell surface receptor-like protein with a signal peptide sequence at the N-terminal for protein secretion and an extracellular domain and intracellular domain separated by a transmembrane sequence. TMEM108 is highly overexpressed in NB tumor samples and its overexpression significantly predicts poor patient outcome in the Versteeg-88 data set (R2: http://r2.amc.nl). TMEM108 is a completely uncharacterized gene that is enriched in NB tumors and cell lines. In our preliminary studies, we have found that knockdown or knockout of TMEM108 expression caused a cell proliferation defect in one MYCN-amplified and one MYCN-non-amplified NB cell lines. In addition, we also found that overexpression of TMEM108 mutant (mt) with the deletion of its intracellular domain inhibited NB cell proliferation compared to vector control and TMEM108 full-length wild-type (wt). Rabbit polyclonal antibodies targeting its extracellular domain inhibited NB cell proliferation in culture and tumor growth in an orthotopic xenograft mouse model. These findings strongly suggest that TMEM108 mediates an oncogenic signaling pathway in NB cells. Therefore, targeting TMEM108 extracellular domain by an inhibitory antibody or its downstream signaling pathway has a great potential to be eastablished as novel treatment options for NB patients. The central hypothesis of this work is that TMEM108 is an ideal molecular target in NB for an antibody- based therapy. The proposed experiments will test this hypothesis by determining the effect of TMEM108 inhibition on NB tumor growth in cell culture and in an orthotopic mouse model. The specific aims for this project are: 1) to determine the function of TMEM108 in the regulation of NB malignancy; and 2) to determine the therapeutic potential of TMEM108 inhibition in vivo. Targeting TMEM108 is a novel concept in the future treatment of NB. The proposed project, if successful, will establish TMEM108 as a therapeutic target in NB. TMEM108 inhibition may serve not only as a stand-alone therapy but also as an effective adjunct to current chemotherapeutic regimens for treating this aggressive pediatric malignancy.

神经母细胞瘤（NB）是儿童中最常见的颅外恶性实体瘤，导致 超过 15% 的儿童癌症相关死亡。尽管疾病结果总体有所改善， MYCN 扩增 (MYCNA) NB 在很大程度上仍然是一种无法治愈的疾病。与成人肿瘤不同，复发性体细胞肿瘤 NB 突变的发生相对较少。因此，致癌信号转导的失调可能 有助于NB肿瘤发生。 该提案将通过定义跨膜蛋白的作用和调节来实现这一目标 108 （TMEM108）在 NB 恶性肿瘤中的作用，并检查 TMEM108 抑制对 NB 细胞增殖和 原位小鼠模型中的肿瘤生长。 TMEM108 是一种潜在的细胞表面受体样蛋白，具有 N 端的信号肽序列用于蛋白质分泌以及胞外结构域和胞内结构域 由跨膜序列分隔的结构域。 TMEM108 在 NB 肿瘤样本中高度过表达 在 Versteeg-88 数据集中，其过度表达可显着预测患者预后不良（R2： http://r2.amc.nl）。 TMEM108 是一种完全未表征的基因，在 NB 肿瘤和细胞系中富集。 在我们的初步研究中，我们发现TMEM108表达的敲低或敲除会导致 一种 MYCN 扩增和一种 MYCN 非扩增 NB 细胞系中的细胞增殖缺陷。此外，我们还 发现TMEM108突变体（mt）的过度表达及其胞内结构域的缺失抑制了NB 与载体对照和 TMEM108 全长野生型 (wt) 相比，细胞增殖情况。兔多克隆 靶向其胞外结构域的抗体抑制培养物中的 NB 细胞增殖和肿瘤生长 原位异种移植小鼠模型。这些发现强烈表明 TMEM108 介导致癌作用 NB细胞中的信号通路因此，通过抑制性抗体或靶向 TMEM108 胞外结构域 其下游信号通路具有成为 NB 新型治疗选择的巨大潜力 患者。 这项工作的中心假设是 TMEM108 是 NB 中抗体的理想分子靶标 为基础的治疗。拟议的实验将通过确定 TMEM108 的效果来检验这一假设 对细胞培养物和原位小鼠模型中 NB 肿瘤生长的抑制作用。该项目的具体目标 是：1)确定TMEM108在调节NB恶性肿瘤中的功能； 2) 确定 TMEM108 抑制的体内治疗潜力。 靶向 TMEM108 是未来 NB 治疗的一个新概念。拟议的项目如果成功的话 将把TMEM108确立为NB的治疗靶点。 TMEM108 抑制不仅可以作为独立的 疗法，同时也可作为当前化疗方案的有效辅助手段来治疗这种侵袭性的癌症 小儿恶性肿瘤。