Sarcomas primarily affect children and young adults. For pediatric oncologists, sarcomas are a major problem. Most are extremely aggressive and current protocols of surgery, radiation and chemotherapy are not adequate. Significant improvement for sarcoma treatment will require a detailed understanding of the genetic and epigenetic factors responsible for their progression. Each sarcoma is likely to need its own specific molecular-based therapies. To achieve these goals, will likely require generating a mouse model of the human cancer that accurately simulates the human condition in order to increase the information base for each sarcoma. The criterion to establish a ?good? mouse model for human cancers is now very rigorous. Each human cancer is classified by a genetic fingerprint comprised of the expression profile of thousands of genes. Having established authenticity of the mouse model, it can be used to identify the genetic events responsible for tumor progression. Having in turn identified the genetic players, selected components can be used as targets to generate a more rational approach to therapeutic development. We have successfully modeled alveolar rabdomyosarcoma, synovial sarcoma, clear cell sarcoma and alveolar soft-parts sarcoma. We will use selected mouse models to determine the secondary genetic events responsible for sarcoma progression. The contribution of the identified secondary events to malignancy will be genetically assessed in cell lines derived from the respective tumors as well as in the mouse models themselves. We also propose to generate improved third generation mouse models of sarcomas that initiate cancer by inducing the appropriate chromosomal translocation in their cell of origin, rather than utilizing conditional expression of the fusion gene in selected tissues. These third generation mouse models should provide a significant improvement over current conditional expression mouse models by much more closely recapitulating the cancer etiology observed in humans.

Public Health Relevance

The grant proposal is directed at modeling human sarcomas in the mouse. This includes determining the genetic events for initiation and progression of the sarcoma, as well as using the mouse model as a platform for the development of new therapeutic approaches for more effective management of the disease in humans.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
9R01CA210165-41A1
Application #
9172963
Study Section
Development - 2 Study Section (DEV2)
Program Officer
Witkin, Keren L
Project Start
1976-12-01
Project End
2021-08-31
Budget Start
2016-09-07
Budget End
2017-08-31
Support Year
41
Fiscal Year
2016
Total Cost
$468,711
Indirect Cost
$154,140
Name
University of Utah
Department
Genetics
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
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Straessler, Krystal M; Jones, Kevin B; Hu, Hao et al. (2013) Modeling clear cell sarcomagenesis in the mouse: cell of origin differentiation state impacts tumor characteristics. Cancer Cell 23:215-27