Rapamycin is a clinically approved immunosuppressive agent that has displayed significant antitumor activities in both rodent model systems and clinical cancer trials. The cellular activities of rapamycin reflect the inhibition of a single protein target, termed the mammalian Target of Rapamycin (mTOR). This large (approximately 290 kD) protein kinase is a member of a novel family of signaling proteins termed phosphoinositide (PI) 3-kinase related kinases, which collectively play key roles in cell growth control and genome surveillance in mammalian cells. Accumulating evidence suggests a strong link between deregulated signaling through the PI 3-kinase - AKT pathway and the sensitivity of cancer cells to the anti-proliferative effects of rapamycin. Aberrant PI 3-kinase signaling is characteristic of many late-stage, aggressive tumors, including glioblastoma, melanoma, and cancers of the prostate and breast. The overall goals of this project are define the signaling functions of mTOR in cancers, and to further understand the impact of rapamycin on mTOR-dependent responses relevant to cancer progression. In addition, we intend to explore in detail the interplay between the PI 3-kinase -mTOR signaling pathway and hypoxic adaptation, a key step in tumorigenesis.
The specific aims of the current proposal are: (1) to compare the effects of rapamycin versus genetically-induced mTOR deficiency on cancer cell proliferation and tumorigenic activity, (2) to define the roles of mTOR in hypoxia-induced HIF-1alpha accumulation in cancer cells, and (3) to examine the role of hypoxia-induced factor (HIF)-1 inhibition in the anticancer activity of rapamycin.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA076193-07
Application #
6712826
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Forry, Suzanne L
Project Start
1997-12-08
Project End
2008-02-29
Budget Start
2004-03-01
Budget End
2005-02-28
Support Year
7
Fiscal Year
2004
Total Cost
$336,000
Indirect Cost
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Liu, Enbo; Knutzen, Christine A; Krauss, Sybille et al. (2011) Control of mTORC1 signaling by the Opitz syndrome protein MID1. Proc Natl Acad Sci U S A 108:8680-5
Katiyar, Samiksha; Liu, Enbo; Knutzen, Christine A et al. (2009) REDD1, an inhibitor of mTOR signalling, is regulated by the CUL4A-DDB1 ubiquitin ligase. EMBO Rep 10:866-72
Chiang, Gary G; Abraham, Robert T (2007) Targeting the mTOR signaling network in cancer. Trends Mol Med 13:433-42
Howes, Amy L; Chiang, Gary G; Lang, Elizabeth S et al. (2007) The phosphatidylinositol 3-kinase inhibitor, PX-866, is a potent inhibitor of cancer cell motility and growth in three-dimensional cultures. Mol Cancer Ther 6:2505-14
Liu, Mei; Howes, Amy; Lesperance, Jacqueline et al. (2005) Antitumor activity of rapamycin in a transgenic mouse model of ErbB2-dependent human breast cancer. Cancer Res 65:5325-36
Chiang, Gary G; Abraham, Robert T (2005) Phosphorylation of mammalian target of rapamycin (mTOR) at Ser-2448 is mediated by p70S6 kinase. J Biol Chem 280:25485-90
Chiang, Gary G; Abraham, Robert T (2004) Determination of the catalytic activities of mTOR and other members of the phosphoinositide-3-kinase-related kinase family. Methods Mol Biol 281:125-41
Edinger, Aimee L; Linardic, Corinne M; Chiang, Gary G et al. (2003) Differential effects of rapamycin on mammalian target of rapamycin signaling functions in mammalian cells. Cancer Res 63:8451-60
Hudson, Christine C; Liu, Mei; Chiang, Gary G et al. (2002) Regulation of hypoxia-inducible factor 1alpha expression and function by the mammalian target of rapamycin. Mol Cell Biol 22:7004-14
McMahon, Lloyd P; Choi, Kin M; Lin, Tai-An et al. (2002) The rapamycin-binding domain governs substrate selectivity by the mammalian target of rapamycin. Mol Cell Biol 22:7428-38

Showing the most recent 10 out of 16 publications