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: 10565939
• 负责人: Erxi Wu
• 金额: $ 21.79万
• 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/10565939
• 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; Categories; 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; 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; novel therapeutic intervention; nucleolin; patient population; patient stratification; 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.

项目总结/摘要 神经母细胞瘤（NB）从交感神经系统的未成熟神经细胞发展而来，因此，它们可以是神经母细胞瘤。 发现任何地方沿着交感神经系统，虽然大多数出现在肾上腺。NB是 是婴儿中最常诊断的实体瘤之一，也是儿童死亡的主要原因， 实体瘤，占儿童早期所有恶性相关死亡的15%。临床中的主要障碍 NB管理的主要问题是治疗抗性和当前治疗的不期望的治疗后副作用。 近年来的研究进展表明，这些患者的治疗耐药性归因于 NB中存在癌症干细胞（CSC），这些细胞对常规抗癌药物（如 卡铂和环磷酰胺。然而，努力开发新的有效的分子制剂， 复发和治疗抗性仍然不能令人满意。要想成功地 治疗学的一个重要特征是NB的异质性：我们认为作为单一疾病实体的一种疾病， 生物学异质性条件，汇聚在共同的临床表型。方面的阐述 基因型（例如，MYCN扩增）、风险分层（例如，低、中、高），和临床行为（例如， 疾病分期和组织学），NB是异质性的。基于上述需求，我们将探索 NB的新治疗策略。虽然许多不同的途径和CSC生物标志物已经被牵连， NB，我们已经开发了一种新的范式来开发NB的有效治疗方法。首先，我们展示了 盐霉素对NB细胞和NB-CSC表现出强的细胞毒性。此外，我们令人信服地证明， 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CD 34相关， 在NB细胞中。NCL和CD 34在NB中很少被探索。这些令人兴奋的发现促使我们研究治疗性药物， 盐霉素的活性和对这种治疗有反应的患者与对这种治疗无反应的患者进行分层的可能性， 对其结合靶点NCL表达的影响，并探讨盐霉素作为潜在药物的作用机制 NB治疗为NB患者开发新的临床有效的治疗策略仍然是一个挑战。 这是一项具有挑战性的任务，也是拟议项目的长期目标。拟议战略的近期总体目标 研究盐霉素的治疗效果，可能通过治疗对患者进行分层 反应的基础上NCL表达，并探讨盐霉素的细胞毒机制， NB在体外和体内。我们的中心假设是盐霉素通过与细胞内的 靶点，其启动涉及NB细胞生长和肿瘤块形成的控制的信号级联。这 该项目将探讨1）NCL如何介导NB中盐霉素的抗肿瘤作用，以及2）NCL- 盐霉素体内外抗肿瘤作用中CD 34启动子的相互作用圆满完成 本研究的目的是提供一个强有力的概念框架，为继续追求新的有效的 抗癌剂和NB的转化治疗靶点。