Characterization and Targeting of p53 Ubiquitination in Neuroblastoma.
Neuroblastoma is an aggressive pediatric cancer that accounts for more than 15% of all pediatric cancer deaths. Currently we treat advanced disease with high dose chemotherapy, radiation therapy and surgery and despite these toxic therapies, cure rates remain less than 40% in children over one year of age. Our laboratory focuses on developing novel biologically specific therapies for neuroblastoma with the hope that these will be more effective and less toxic.
The major focus of this proposal centers on the tumor suppressor molecule p53 in neuroblastoma. At normal levels, p53 protein’s major role is cell growth inhibition, and at high levels, p53 can lead to programmed cell death (apoptosis). Moreover, a mutation of the p53 gene, with its subsequent down-regulation, has been identified in a number of different cancers. Previously, we have shown that by increasing p53 activity with the non-toxic small molecule Nutlin, neuroblastoma cells are efficiently killed by the process of apoptosis. Another way to increase p53 activity is to prevent its degradation within neuroblastoma cells. This will lead to increased levels of p53 and easier activation of cell death. Typically the p53 molecule is degraded by a mechanism called ubiquitination. This involves the binding of ubiquitin molecules to p53 by enzymes called E-3 ubiquitin ligases, which causes the protein to be rapidly destroyed in the cell. From preliminary data we show that neuroblastoma appears to have a uniquely active p53 ubiquitination pathway that is controlled by E-3 ligases. We believe that through better understanding of these ligases which are active in p53 degradation in neuroblastoma, we may be able to inhibit or destroy them, leading to increased p53 levels and subsequent cell death in neuroblastoma tumors.
This novel approach to therapy may then be combined with standard chemotherapy, which will allow us to use less toxic chemotherapy and yet kill neuroblastoma more efficiently. Our laboratory has expert knowledge in studying apoptosis and the process of p53 degradation in neuroblastoma. We also now have preliminary data, which indicates the best ligases to target initially. Completion of the work proposed herein will provide preclinical data supporting the development of this therapeutic approach.