This application will define mechanisms of rapamycin-mediated tumor onset delay or prevention and will dissect mTOR effects directly on the tumor versus immune cell effects. It addresses Provocative Question 5: defining mechanisms of action of drugs used for other purposes. We challenge the paradigm that mTOR inhibition reduces or prevents cancer by direct effects on tumors through mTOR growth and metabolic effects, and explore the potential for mTOR inhibitors to prevent cancer through mTOR-mediated immune effects. We hypothesize that mTOR inhibition with oral rapamycin delays or prevents cancer onset in part through immune mechanisms, and will test concepts in a well-defined carcinogen-induced skin cancer model in which T cells and IFN-? are important protective agents and in which mTOR inhibition prevents cancer. Mice will have tumor induced with dimethylbenz(a)-anthracene (DMBA) plus the promoter 12-O- tetradecanoylphorbol-13-acetate (TPA) and will be treated with oral rapamycin or control. Time to tumor onset, malignant change and tumor size and effects on tumor immune surveillance will be studied as will mTOR signaling in tumor versus other cells.
Aim 1 Test the hypothesis that T cells contribute to oral rapamycin- mediated cancer prevention.
Aim 2 Test the hypothesis that IFN-? contributes to oral rapamycin- mediated cancer prevention.
Aim 3 Test the hypothesis that rapamycin prevents cancer by direct effects on tumor cells. mTOR inhibition directly in tumors cell is not mutually exclusive with immune mechanisms. Relevance: Cancer is the number one killer in the US. Cure rates for advanced cancers have changed little in the past 50 years. Prevention is more cost effective and broadly applicable than treatments. We thus propose a novel, safe, broad spectrum approach to cancer prevention using rapamycin as a potential first-in-class agent.

Public Health Relevance

This application will use a well-characterized carcinogen-induced mouse model for skin cancer to test whether immune effects of rapamycin contribute to its cancer prevention properties. This model mirrors important tumor signaling and host immune defense pathways involved in major human cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA170491-02
Application #
8538910
Study Section
Special Emphasis Panel (ZCA1-SRLB-D (M1))
Program Officer
Umar, Asad
Project Start
2012-09-01
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
2
Fiscal Year
2013
Total Cost
$152,826
Indirect Cost
$50,601
Name
University of Texas Health Science Center San Antonio
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
Hasty, Paul; Livi, Carolina B; Dodds, Sherry G et al. (2014) eRapa restores a normal life span in a FAP mouse model. Cancer Prev Res (Phila) 7:169-78
Sharp, Zelton Dave; Curiel, Tyler Jay; Livi, Carolina Becker (2013) Chronic mechanistic target of rapamycin inhibition: preventing cancer to delay aging, or vice versa?. Interdiscip Top Gerontol 38:1-16