) Our previous NCDDG assessed and developed farnesyltransferase inhibitors (FTls) as anti-Ras drugs. Fromthose studies arose an appreciation that inhibitors of protein geranylgeranyltransferase I (GGTls) may also be useful as anti-Ras and anti-cancer drugs. The overall long-term goal of this NCDDG is to develop GGTls as novel anti-cancer drugs. Three key observations link geranylgeranylated (GG) proteins to Ras and cancer development. First, FTI-treated K-Ras and N-Ras proteins become alternatively prenylated by GG and escape the inhibitory action of FTls. Second, the Ras-related proteins R-Ras and R-Ras2/TC21 are GG-modified and their aberrant activation can promote tumorigenic transformation and tumor cell invasion. Third, members ofthe Rho family of Ras-related proteins (Racl, RhoA, and Cdc42) are GG-modified, are required for the transforming actions of Ras and other oncoproteins, and their aberrant activation can cause tumor cell invasion and metastasis. Finally, recent work from this NCDDG showed that GGTls can arrest human tumor cell growth in vitra and reduce tumorigenicity in viva. Taken together, these observations support the importance of targeting the function of GG-modified proteins for cancer treatment. The two broad goals of Program #3 of this NCDDG are (a) to determine if specific GG-modified members of the Ras superfamily of proteins are targets of GGTIs, and (b) to identify genes whose expression are regulated by geranylgeranylated proteins and are therefore targets of GGTI-mediated growth inhibition.
Three specific aims are proposed: (1) to determine if R-Ras and TC21 are targets for GGTI-mediated growth inhibition, (2) to determine if Racl, RhoA, and Cdc42 are targets for GGTI-mediated growth inhibition, and (3) to identify genes whose expression are altered by GGTI-mediated inhibition of geranylgeranylation and cellular proliferation. The GGTls that are developed in Program#1 will be essential for our studies and the in vitro and in vivo analyses of GGTI activity proposed for Program #2 will strongly complement our analyses.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program--Cooperative Agreements (U19)
Project #
2U19CA067771-06
Application #
6352768
Study Section
Project Start
2000-09-18
Project End
2001-04-30
Budget Start
Budget End
Support Year
6
Fiscal Year
2000
Total Cost
Indirect Cost
Name
University of South Florida
Department
Type
DUNS #
City
Tampa
State
FL
Country
United States
Zip Code
33612
Patel, R A; Liu, Y; Wang, B et al. (2014) Identification of novel ROCK inhibitors with anti-migratory and anti-invasive activities. Oncogene 33:550-5
Vigil, Dominico; Kim, Tai Young; Plachco, Ana et al. (2012) ROCK1 and ROCK2 are required for non-small cell lung cancer anchorage-independent growth and invasion. Cancer Res 72:5338-47
Li, Rongshi; Martin, Mathew P; Liu, Yan et al. (2012) Fragment-based and structure-guided discovery and optimization of Rho kinase inhibitors. J Med Chem 55:2474-8
Pireddu, Roberta; Forinash, Kara D; Sun, Nan N et al. (2012) Pyridylthiazole-based ureas as inhibitors of Rho associated protein kinases (ROCK1 and 2). Medchemcomm 3:699-709
Mitin, Natalia; Roberts, Patrick J; Chenette, Emily J et al. (2012) Posttranslational lipid modification of Rho family small GTPases. Methods Mol Biol 827:87-95
Patel, Ronil A; Forinash, Kara D; Pireddu, Roberta et al. (2012) RKI-1447 is a potent inhibitor of the Rho-associated ROCK kinases with anti-invasive and antitumor activities in breast cancer. Cancer Res 72:5025-34
Berndt, Norbert; Sebti, Saïd M (2011) Measurement of protein farnesylation and geranylgeranylation in vitro, in cultured cells and in biopsies, and the effects of prenyl transferase inhibitors. Nat Protoc 6:1775-91
Cook, Danielle R; Solski, Patricia A; Bultman, Scott J et al. (2011) The ect2 rho Guanine nucleotide exchange factor is essential for early mouse development and normal cell cytokinesis and migration. Genes Cancer 2:932-42
Berndt, Norbert; Hamilton, Andrew D; Sebti, Saïd M (2011) Targeting protein prenylation for cancer therapy. Nat Rev Cancer 11:775-91
Xu, Dapeng; Allsop, Stephen A; Witherspoon, Sam M et al. (2011) The oncogenic kinase Pim-1 is modulated by K-Ras signaling and mediates transformed growth and radioresistance in human pancreatic ductal adenocarcinoma cells. Carcinogenesis 32:488-95

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