Rady’s Children’s Hospital – Hyundai Hope On Wheels

2019

Scholar Grant

Peter Zage

San Diego, CA

Title: Cellular Networks in Neuroblastoma Differentiation

Executive Summary:
While induction of differentiation is an effective strategy for neuroblastoma treatment, the mechanisms underlying the process of neuroblastoma differentiation are not well understood, and improved understanding of these mechanisms will likely identify novel targets for therapies that are critically needed for children with high-risk and relapsed neuroblastoma. The activity of a number of growth factor receptors (GFRs) and intracellular signaling pathways have been associated with neuroblastoma differentiation, but the coordinated roles of GFR expression and downstream intracellular signaling network activity in neuroblastoma differentiation have not been fully delineated. UBE4B is a ubiquitin ligase required for GFR trafficking and degradation, and we have previously shown that low UBE4B expression is associated with poor neuroblastoma patient outcomes, reduced tumor cell differentiation, and increased intracellular signaling activity, suggesting that intracellular signaling networks regulated by UBE4B-mediated GFR trafficking may play a role in neuroblastoma differentiation. We believe that neuroblastoma differentiation is regulated by a coordinated network of intracellular signaling pathways and that these signaling networks represent potential therapeutic targets to develop novel agents that induce neuroblastoma differentiation. We propose unbiased analyses of transcriptomic datasets using a Boolean mathematical tool to evaluate the roles of intracellular signaling networks in neuroblastoma differentiation, and we will then validate the potential role of these pathways and networks as mediators of differentiation and potential therapeutic targets in neuroblastoma cells and tumors. The results of these studies will provide a better understanding of neuroblastoma pathogenesis and mechanisms underlying responses to treatment, likely leading to novel targets for neuroblastoma therapy.

• Our primary goals therefore are to identify the signals and pathways that control neuroblastoma tumor differentiation and to determine whether these pathways can be inhibited to improve the survival rates of children with high-risk neuroblastoma
• We propose to use a new mathematical tool to identify the key networks that control neuroblastoma tumor differentiation
• We will determine whether and how the ubiquitin ligase UBE4B controls neuroblastoma differentiation and the effectiveness of inhibiting networks controlled by UBE4B against neuroblastoma tumors