Neuroblastoma (NBL), a devastating neurologic solid tumor of children, accounts for 15% of yearly pediatric oncologic deaths. While most NBL patients are cured with multi-modal chemotherapy, 30% carry a genetic mutation -- MYCN oncogene amplification, which is tightly linked to therapeutic failure, tumor progression and relapse. The broad goal of this study is to assess the role of MYCN inhibition in preventing the progression of MYCN-amplified tumors in this high risk group of patients with few therapeutic choices. The study focuses in two specific aims on a novel role for the PI3-kinase pathway in stabilization of Mycn protein, and the efficacy of specific low-molecular weight pathway inhibitors for preventing NBL cell proliferation and tumor progression. The significance of the work is in the potential identification of a practical new approach to therapy of high-risk patients, and in the development of a new NBL transgenic mouse model ideal for the pre-clinical testing of new agents as they are developed by others in the field.
In aim I, the role of the PI3-kinase pathway in regulating Mycn protein expression is mechanistically studied in vitro using established MYCN-amplified and unamplified cell lines. Specific attention is focused on Mycn protein phosphorylation, using two unique reagents: an antibody to phospho-Mycn and phospho-Mycn point mutants. The effects of Mycn inhibition on cell cycling, proliferation, apoptosis and differentiation. The effects of pathway inhibitors are compared to that of specific MYCN ablation by RNAi.
In aim II, the effects of pharmacologic Mycn suppression on NBL tumor growth is assessed in human xenografts, a native TH-MYCN transgenic mouse model of NBL, and a new TRE-MYCN-Luc model of NBL in which MYCN expression is regulable and tumors are detectable in vivo using Xenogen imaging. The effects of pathway inhibition are compared to that of regulated suppression of MYCN expression using doxycycline (Dox) in the TRE-MYCN-Luc model and in xenografts of SHEP-tet21 cells, which suppress MYCN expression in response to Dox.
| Chesler, Louis; Goldenberg, David D; Collins, Rodney et al. (2008) Chemotherapy-induced apoptosis in a transgenic model of neuroblastoma proceeds through p53 induction. Neoplasia 10:1268-74 |
| Chesler, Louis; Goldenberg, David D; Seales, Isha T et al. (2007) Malignant progression and blockade of angiogenesis in a murine transgenic model of neuroblastoma. Cancer Res 67:9435-42 |
| Chesler, Louis; Schlieve, Chris; Goldenberg, David D et al. (2006) Inhibition of phosphatidylinositol 3-kinase destabilizes Mycn protein and blocks malignant progression in neuroblastoma. Cancer Res 66:8139-46 |
