Increased polyamine synthesis and inflammation are associated with intraepithelial neoplasia, which are risk factors for various types of cancer development in humans. Ornithine decarboxylase (ODC) is highly expressed in many cancer cell types and promotes growth and tumor formation. Elevated ODC activity in carcinogenesis model systems and neoplastic tissues suggests that this enzyme is a valid target for chemoprevention. Difluoromethylornithine (DFMO) is an approved FDA drug that acts as an irreversible and specific ODC inhibitor, and reportedly prevents carcinogenesis, especially in the skin and colon. However, high doses of DFMO in humans are associated with various degrees of hearing loss. By using computational biology with the BlueGene/L supercomputer, we have found at least one small molecule allosteric inhibitor of ODC that is less toxic and more potent than DFMO in suppressing skin and colon carcinogenesis. In this application, we propose to use state of the art technologies to identify and test additional novel, nontoxic small molecule inhibitors of ODC. These approaches include determining binding, binding affinities, specific binding sites and resulting structural changes by computation simulation using the BlueGene/L Supercomputer and our newly acquired GPU system, and performing protein binding assays, cell transformation assays and in vivo animal experiments, including the 2-stage mouse skin carcinogenesis model and the APCmin mouse model. Through these studies, we will develop more effective agents targeting ODC with fewer side effects for the chemoprevention of skin cancer and colon cancer.

Public Health Relevance

Ornithine decarboxylase (ODC) is an enzyme that highly expressed in many cancer cell types and promotes growth and tumor formation. Difluoromethylornithine (DFMO) is an approved FDA drug that acts as an irreversible and specific ODC inhibitor and appears to prevent skin and colon. However, high doses of DFMO in humans cause hearing loss. Thus identifying new potent, nontoxic ODC inhibitors is extremely important.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA166011-05
Application #
9194388
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Perloff, Marjorie
Project Start
2013-01-01
Project End
2017-12-31
Budget Start
2017-01-01
Budget End
2017-12-31
Support Year
5
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Biochemistry
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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