Neuroblastoma is the most common solid tumor in children outside of the brain and spinal cord. Half of affected patients have high risk disease at diagnosis and have <40% chance at cure despite aggressive chemotherapy, surgery and transplant, so new therapies are desperately needed. There is already evidence that the Notch pathway may play one or more roles in the growth and survival of neuroblastoma cells. However, it is not clear how uniform the effects of Notch signaling are, and whether Notch signaling plays an important role in neuroblastoma stem cells. Furthermore it is not known whether targeting the Notch pathway would be a promising therapeutic approach. Our preliminary data suggest that enhancing Notch signaling, and more specifically HES gene activity, leads to growth arrest and differentiation of neuroblastoma cell lines. We believe that Notch/HES signaling may inhibit neuroblastoma stem cell growth and survival, while limiting tumor-forming ability. Given this, our long-term goal is to develop Notch enhancing agents for the potential use in children with neuroblastoma. However, to achieve this goal we propose a series of experiments which will determine 1) whether it is likely that patient samples and a newly-described neuroblastoma stem cell population will respond to Notch signaling, 2) whether we can use a Notch-stimulating agents to induce growth arrest and differentiation in neuroblastoma cell lines and stem cells, and 3) whether stimulating Notch signaling in these cells can interfere with tumor growth and metastasis.
In Aim 1 we will determine what the effects of enhancing and inhibiting the Notch/HES pathways are in neuroblastoma cell lines and stem cells.
In Aim 2 we will test these findings in mice harboring human neuroblastoma tumors, measuring the effects of Notch signaling on tumor formation, growth, and differentiation. Here we will determine whether a Notch-enhancing peptide is effective and promising as a novel therapeutic approach.
In Aim 3 we will examine the Notch/HES pathways using patient samples, a panel of cell lines and newly described neurosphere neuroblastoma stem cells. Through these experiments we will gain knowledge regarding the role(s) of Notch signaling in neuroblastoma stem cells, and will determine the effectiveness and feasibility of using a Notch-directed approach for the treatment of neuroblastoma.
Neuroblastoma is responsible for over 15% of all childhood cancer deaths and new therapies are needed. The Notch signaling pathway may play a role in neuroblastoma formation and/or growth through effects on neuroblastoma cancer stem cells. In this proposal, we will investigate this role with the long term goal of using Notch modulating agents as a novel treatment for neuroblastoma.
| Zage, Peter E; Nolo, Riitta; Fang, Wendy et al. (2012) Notch pathway activation induces neuroblastoma tumor cell growth arrest. Pediatr Blood Cancer 58:682-9 |
