Friday, November 22, 2024
11/22/2024
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.
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