) 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.
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