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.

项目摘要/摘要 神经母细胞瘤（NB）是由交感神经系统的未成熟神经细胞发展出来的，因此它们可以是 尽管大部分出现在肾上腺中，但沿着交感神经系统的任​​何地方都可以找到。 NB是 是婴儿中最常见的实体瘤之一，是儿童死亡的主要原因 实体瘤，占儿童早期所有与恶性肿瘤有关的死亡的15％。临床的主要障碍 NB的治疗是治疗性的耐药性，也是当前疗法的治疗后副作用。 近年来的研究进展表明，这些患者的治疗耐药性归因于 在常规抗癌药物（例如 卡铂和环磷酰胺。但是，为NB开发新的有效分子剂的努力 复发和抗药性仍然不令人满意。取得成功的一个关键障碍 治疗剂是NB的异质性：我们认为是一种单一疾病实体的疾病实际上表现出 在常见的临床表型上汇聚的生物异质条件。从 基因型（例如MYCN扩增），风险分层（例如，低，中级，高）和临床行为（例如， 疾病和组织学的阶段），NB是异质的。基于上述需求，我们要探索 NB的新治疗策略。虽然在 NB，我们已经开发了一种新型的范式来开发NB的有效治疗方法。首先，我们表明 盐霉素针对NB细胞和NB-CSC表现出强大的细胞毒性。此外，我们令人信服地证明了 该核醇蛋白（NCL）是NB细胞中盐霉素的结合蛋白。然后，我们发现NCL与CD34相关 在NB细胞中。 NB很少在NB中探索NCL和CD34。这些令人兴奋的发现促使我们学习治疗 盐霉素的活性以及分层的潜力，而不是对这种疗法的反应 关于其结合靶标NCL的表达，并探索盐霉素的药物作用机制 NB治疗。为NB患者开发新的临床有效治疗策略仍然 具有挑战性的任务，是拟议项目的长期目标。提议的直接总体目标 工作是研究盐霉素的治疗作用，有可能通过治疗对患者进行分层 基于NCL表达的反应并探索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结合起作用 启动信号级联的目标涉及控制NB细胞生长和肿瘤大体形成。这 项目将探索1）NCL如何介导NB中盐霉素的抗肿瘤作用，以及2）NCL-的作用 CD34启动子在体外和体内的抗肿瘤作用中的相互作用。成功完成 预计这项研究将为继续追求新颖有效的概念框架提供一个强大的概念框架 NB的抗癌剂和翻译治疗靶标。