The mechanisms of cancer development in children are poorly understood. Molecular analysis of the recurrent chromosomal translocations found in many pediatric solid tumors has identified unique fusion oncogenes for each tumor type. Ewing's sarcoma is a pediatric tumor of uncertain histologic origin that is defined by the presence of a specific chromosomal rearrangement, t(11;22)(q24;q12). This translocation generates the EWS/FLI fusion oncogene. While EWS/FLI expression appears to be required for Ewing's sarcoma development, it is unlikely to be the only genetic alteration present in this tumor. The goal of this proposal, therefore, is to identify additional genetic events that are required in the genesis of Ewing's sarcoma. While expression of EWS/FLI in immortalized murine fibroblasts results in cellular transformation, our preliminary work demonstrates that expression of EWS/FLI in primary human fibroblasts results in growth arrest. Our hypothesis is that primary cells have growth-inhibitory pathways in place that prevent neoplastic transformation by oncogenes, and that these pathways are likely to be abrogated in Ewing's sarcoma. We propose a multifaceted approach to identify these pathways. First, we will use data obtained from expression analysis to identify and validate pathways that mediate this growth arrest. Next, we will identify new pathways by suppressor screening. Finally, we will determine whether these pathways are altered in Ewing's sarcoma clinical samples to identify which are biologically relevant to the development of this tumor. The results generated by these studies will not only identify cooperative mutations important for Ewing's sarcoma development, but will also provide unique insights into the mechanisms that primary cells use to inhibit oncogenic transformation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08CA096755-06
Application #
6999329
Study Section
Subcommittee G - Education (NCI)
Program Officer
Myrick, Dorkina C
Project Start
2002-07-31
Project End
2007-06-30
Budget Start
2006-02-03
Budget End
2006-12-31
Support Year
6
Fiscal Year
2006
Total Cost
$135,837
Indirect Cost
Name
University of Utah
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Gangwal, Kunal; Sankar, Savita; Hollenhorst, Peter C et al. (2008) Microsatellites as EWS/FLI response elements in Ewing's sarcoma. Proc Natl Acad Sci U S A 105:10149-54
Hancock, Jeffrey D; Lessnick, Stephen L (2008) A transcriptional profiling meta-analysis reveals a core EWS-FLI gene expression signature. Cell Cycle 7:250-6
Stegmaier, Kimberly; Wong, Jenny S; Ross, Kenneth N et al. (2007) Signature-based small molecule screening identifies cytosine arabinoside as an EWS/FLI modulator in Ewing sarcoma. PLoS Med 4:e122
Smith, Richard; Owen, Leah A; Trem, Deborah J et al. (2006) Expression profiling of EWS/FLI identifies NKX2.2 as a critical target gene in Ewing's sarcoma. Cancer Cell 9:405-16
Braunreiter, Chi L; Hancock, Jeffrey D; Coffin, Cheryl M et al. (2006) Expression of EWS-ETS fusions in NIH3T3 cells reveals significant differences to Ewing's sarcoma. Cell Cycle 5:2753-9
Owen, Leah A; Lessnick, Stephen L (2006) Identification of target genes in their native cellular context: an analysis of EWS/FLI in Ewing's sarcoma. Cell Cycle 5:2049-53
Kinsey, Michelle; Smith, Richard; Lessnick, Stephen L (2006) NR0B1 is required for the oncogenic phenotype mediated by EWS/FLI in Ewing's sarcoma. Mol Cancer Res 4:851-9
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