FTIs have been shown to inhibit the growth of human tumors in preclinical animal models and are presently in clinical trials but their mechanism of antitumor activity is unknown. The hypothesis upon which this proposal is based is that FTIs inhibit tumor growth by inducing apoptosis through inhibition of phosphatidyl inositol-3-kinase (PI3K)/AKT-mediated survival and adhesion pathways. This hypothesis will be tested through the following specific aims: 1) To determine the involvement of the AKT survival pathway in FTI-277-induced apoptosis; 2) To determine the ability of FTI-277 to disrupt PI3-kinase/AKT mediated cell survival and adhesion pathways; 3) To determine the involvement of H-ras, N-ras and K-ras in mediating activation of the PI3K/AKT survival pathways, and their implication in FTI-277-induced apoptosis, and; 4) To determine the involvement of the AKT survival pathway in FTI-277 antitumor activity in the nude mouse human tumor xenograft model. Two highly potent and selective but structurally unrelated FTIs (L-739,750 and SCH66336) will be used to confirm these findings.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA085709-04
Application #
6696735
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Forry, Suzanne L
Project Start
2001-01-18
Project End
2005-12-31
Budget Start
2004-01-01
Budget End
2004-12-31
Support Year
4
Fiscal Year
2004
Total Cost
$195,750
Indirect Cost
Name
University of South Florida
Department
Biochemistry
Type
Schools of Medicine
DUNS #
069687242
City
Tampa
State
FL
Country
United States
Zip Code
33612