Salinomycin and its binding protein nucleolin in neuroblastoma

盐霉素及其结合蛋白核仁素在神经母细胞瘤中的作用

• 批准号: 10361595
• 负责人: Erxi Wu
• 金额: $ 18.52万
• 依托单位: BAYLOR RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-07 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10361595
• 关键词: Accounting; Adrenal Glands; Aftercare; Age; American; Antineoplastic Agents; Archives; Behavior; Binding; Binding Proteins; Biological Process; Biology; CD34 gene; CRISPR/Cas technology; Carboplatin; Cell Proliferation; Cessation of life; Chemicals; Child; Childhood; Clinical; Clinical Management; Cyclophosphamide; Data; Development; Diagnosis; Disease; Etoposide; Exhibits; Foundations; Genotype; Goals; Hematopoietic stem cells; Heterogeneity; Histology; In Vitro; Infant; Journals; Link; MYCN gene; Malignant Childhood Neoplasm; Malignant Neoplasms; Mediating; Molecular; Neuroblastoma; Neurons; Pathologic; Pathway interactions; Patients; Population; Proteins; Public Health; Publishing; Recurrence; Recurrent disease; Refractory; Reporting; Research; Resistance; Role; Signal Transduction; Societies; Solid Neoplasm; Specimen; Sympathetic Nervous System; System; Therapeutic; Therapeutic Effect; Therapeutic Studies; Tissues; Treatment Side Effects; United States; Work; anti-cancer; antitumor effect; base; cancer stem cell; cell growth; clinical phenotype; clinically relevant; cytotoxic; cytotoxicity; drug action; early childhood; effective therapy; high risk; in vivo; insight; mortality; mouse model; neuroblast; neuroblastoma cell; novel; nucleolin; patient population; patient stratification; population based; promoter; response; risk stratification; salinomycin; stem cell biomarkers; stemness; therapeutic target; therapy resistant; translational therapeutics; treatment response; treatment strategy; tumor; tumorigenic

Project Summary/Abstract Neuroblastoma (NB) develops from immature nerve cells of the sympathetic nervous system, thus, they can be found anywhere along the sympathetic nervous system, although the majority arise in the adrenal glands. NB is one of the most commonly diagnosed solid tumors in infants, and a leading cause of mortality in children with solid tumors, accounting for 15% of all malignancy-related death in early childhood. Major obstacles in the clinical management of NB are therapy resistance, and undesirable post treatment side effects of current therapies. Research advances during recent years indicate that treatment resistance in these patients is attributable to the presence of cancer stem cells (CSCs) in NBs that are refractory to conventional anti-cancer drugs such as carboplatin and cyclophosphamide. However, efforts to develop new effective molecular agents for NB recurrence and therapy resistance remain unsatisfactory. One critical barrier to achieving successful therapeutics is the heterogeneity of NB: a disorder we think of as a single disease entity exhibits in fact biologically heterogeneous conditions that converge on common clinical phenotypes. From the perspectives of genotype (e.g., MYCN amplification), risk stratification (e.g., low, intermediate, high), and clinical behavior (e.g., stage of disease and histology), NB is heterogeneous. Based on the above mentioned needs, we are to explore new treatment strategies for NB. While many distinct pathways and CSC biomarkers have been implicated in NB, we have developed a novel paradigm to develop an effective treatment for NB. First, we showed that salinomycin exhibits strong cytotoxicity against NB cells and NB-CSCs. Further, we convincingly demonstrated that nucleolin (NCL) is a salinomycin’s binding protein in NB cells. We then found that NCL is linked with CD34 in NB cells. Both NCL and CD34 are rarely explored in NB. These exciting findings prompt us to study therapeutic activity of salinomycin and potential to stratify patients who are versus are not responsive to this therapy based on its binding target NCL’s expression and to explore the mechanisms of drug action of salinomycin as a potential NB therapeutic. Development of new clinically effective treatment strategies for patients with NB remains a challenging task, and is a long-term goal of the proposed project. The immediate overall objective of the proposed work is to investigate the therapeutic effect of salinomycin, potentially to stratify patients by their therapy responses based on NCL expression and explore the underlying cytotoxic mechanism of salinomycin against NB in vitro and in vivo. Our central hypothesis is that salinomycin functions through binding to an intracellular target that initiates a signaling cascade involving the control of NB cell growth and tumor bulk formation. This project will explore 1) how NCL mediates the anti-tumor effects of salinomycin in NB, and 2) the role of the NCL- CD34 promoter interaction in the anti-tumor effects of salinomycin in vitro and in vivo. The successful completion of this study is expected to provide a strong conceptual framework for the continued pursuit of novel effective anticancer agents and translational therapeutic targets for NB.

项目概要/摘要 神经母细胞瘤（NB）由交感神经系统的未成熟神经细胞发展而来，因此，它们可以 尽管大多数出现在肾上腺，但交感神经系统的任​​何地方都可以找到。注意是 婴儿中最常诊断出的实体瘤之一，也是儿童死亡的主要原因 实体瘤占幼儿期所有恶性肿瘤相关死亡的 15%。临床上的主要障碍 NB 的管理包括治疗耐药性和当前疗法的不良治疗后副作用。 近年来的研究进展表明，这些患者的治疗抵抗可归因于 NB 中存在癌症干细胞 (CSC)，这些细胞对传统抗癌药物（如 卡铂和环磷酰胺。然而，努力开发新的有效的 NB 分子制剂 复发和治疗耐药性仍然不令人满意。取得成功的一个关键障碍 治疗学是 NB 的异质性：我们认为是单一疾病实体的疾病实际上表现出 趋于共同临床表型的生物学异质性病症。从以下几个方面来看 基因型（例如 MYCN 扩增）、风险分层（例如低、中、高）和临床行为（例如 疾病阶段和组织学），NB 是异质的。基于上述需求，我们正在探索 NB的新治疗策略。虽然许多不同的途径和 CSC 生物标志物与 NB，我们开发了一种新的范例来开发针对 NB 的有效治疗方法。首先，我们证明了 salinomycin 对 NB 细胞和 NB-CSC 表现出强烈的细胞毒性。此外，我们令人信服地证明了 核仁素 (NCL) 是 NB 细胞中盐霉素的结合蛋白。然后我们发现NCL与CD34相连 在NB细胞中。 NCL 和 CD34 在 NB 中都很少被探索。这些令人兴奋的发现促使我们研究治疗方法 盐霉素的活性以及对基于该疗法的患者进行分层的潜力 对其结合靶点 NCL 的表达进行研究，并探讨盐霉素作为潜在药物的药物作用机制 NB治疗。为 NB 患者开发新的临床有效治疗策略仍然是一个难题 具有挑战性的任务，并且是拟议项目的长期目标。拟议的近期总体目标 工作是研究盐霉素的治疗效果，可能通过治疗对患者进行分层 基于 NCL 表达的反应并探讨盐霉素的潜在细胞毒性机制 NB体外和体内。我们的中心假设是盐霉素通过与细胞内的结合物发挥作用 启动涉及控制 NB 细胞生长和肿瘤块形成的信号级联的靶标。这 该项目将探讨 1) NCL 如何介导盐霉素在 NB 中的抗肿瘤作用，以及 2) NCL-的作用 CD34启动子相互作用在盐霉素体外和体内抗肿瘤作用中的作用。顺利完成 这项研究预计将为继续追求新颖有效的方法提供强有力的概念框架 NB 的抗癌药物和转化治疗靶点。