Neuroblastoma (NB) is a childhood cancer that exhibits either a favorable or an unfavorable phenotype. Twenty percent of NB cases have MYCN amplification, which is strongly associated with older age, advanced stage disease, rapid tumor progression, and the worst disease outcome. However, the significance of MYCN expression in NB has been controversial. We recently demonstrated that NB can be divided into three subgroups based on MYCN expression, MYCN amplification, and patient survival. Group 1 includes those with MYCN amplification and the worst disease outcome. Group 2 and Group 3 are NB lacking MYCN amplification expressing low and high levels of MYCN expression, respectively. Interestingly though, the survival rate of Group 3 is better than that of Group 2. With the forced expression of MYCN in NB cell lines (derived from Group 2) by transfection, there is induced apoptosis and enhanced expression of favorable NB genes. Based on these observations, we hypothesize that high MYCN expression confers the opposite biological consequence in NB depending on whether or not MYCN is amplified. In addition, age-dependent DNA methylation on MYCN binding sites influences how MYCN modulates the behavior of NB. Chemotherapeutic agents that can reduce or enhance MYCN expression in MYCN-amplified or MYCN-non-amplified NB, respectively, would have great impact on therapeutic strategies against these malignant tumors. Specifically, (Aim 1) we will perform comprehensive clinical correlative studies among MYCN expression, tumor stage, patient age, MYCN amplification, 1p and 11q deletion status, and favorable NB gene expression in a large NB cohort by multivariable Cox regression models, and examine the prognostic significance of MYCN expression in subsets of high-risk MYCN-non-amplified NB by Kaplan-Meier analysis and log rank test, (Aim 2) identify MYCN target genes that provide NB with a favorable phenotype (favorable NB gene candidates) by genome wide gene expression profiling and ChIP-on-chip assay, and examine their clinical relevance in NB, (Aim 3) correlate age-dependent DNA methylation patterns and gene expression profiles in four age-based subsets (0- 6, 6-12, 12-18, and >18 months) to gain insight into the "Age Factor" of NB: the younger the patients, the better the outcome, and (Aim 4) examine the efficacy of dexamethasone, a site-specific DNA demethylation inducer in combination with DNA methylation inhibitors (5-Aza-2'- deoxycytidine and RG108) and RAS pathway specific MYCN protein destabilizers in preclinical human NB subcutaneous and metastatic xenograft models.

Public Health Relevance

Future advances in the control of resistant malignant NB cells will be made through modulation of their intrinsic biology. We expect this series of translational research experiments will confirm the critical importance of how MYCN expression could modulate the malignancy of such NB cells. In addition, the results of our experiments will hold promise for the early introduction of favorable NB gene enhancers and MYCN-destabilizers into clinical trials, for example, in the control of minimal residual disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA127571-05
Application #
8324697
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Arya, Suresh
Project Start
2008-09-11
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2012
Total Cost
$316,861
Indirect Cost
$108,190
Name
University of Illinois at Chicago
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
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Ikegaki, Naohiko; Hicks, Sakeenah L; Regan, Paul L et al. (2014) S(+)-ibuprofen destabilizes MYC/MYCN and AKT, increases p53 expression, and induces unfolded protein response and favorable phenotype in neuroblastoma cell lines. Int J Oncol 44:35-43
Silva, Andres; Wang, Jennie; Lomahan, Sarah et al. (2014) Aurora kinase A is a possible target of OSU?03012 to destabilize MYC family proteins. Oncol Rep 32:901-5
Ikegaki, Naohiko; Shimada, Hiroyuki; Fox, Autumn M et al. (2013) Transient treatment with epigenetic modifiers yields stable neuroblastoma stem cells resembling aggressive large-cell neuroblastomas. Proc Natl Acad Sci U S A 110:6097-102
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