Farnesylation is a lipid posttranslational modification that is required for the cancer-causing activity of the oncoprotein Ras. The applicant and others have designed potent and selective farnesyltransferase (FTase) inhibitors (FTI) that block the growth of human tumors in animal models. Many FTIs are presently in phase I and some are about to enter phase II clinical trials. The overall goal of this application is to demonstrate antitumor efficacy of FTI in phase II clinical trials and to enhance our understanding of the mechanism by which inhibition of protein farnesylation results in inhibition of human tumor growth. The hypothesis to be tested is that FTI treatment of patients with multiple myeloma results in tumor growth inhibition, and that the tumors' Ras mutation status is predictive of response. In addition, the applicant will also test the hypothesis that FTI sensitizes human tumors to anticancer drugs in preclinical models. This will be accomplished through the following specific aims: (a) to determine the degree of inhibition of FTase activity and protein farnesylation required for the inhibition of the growth of human tumors. FTI levels in plasma, FTase activity and farnesylation levels of H-, N- and K-Ras and lamin B in tumors and peripheral blood mononuclear cells (PBMN) in human tumor bearing nude mice will be correlated to the antitumor activity of FTI, (b) to determine whether combination therapy with FTI and cytotoxic anti-cancer drugs is more effective than monotherapy. In this aim he will evaluate whether FTI enhance the ability of cisplatin, gemcitabine, taxol, doxorubicin or 5-fluorouracil to induce apoptosis and/or inhibit human tumor growth in nude mice, (c) to determine the antitumor efficacy of FTI in phase II clinical trials. Here the applicant will determine response rates in multiple myeloma cancer patients. These response rates will be correlated to drug levels as well as inhibition of FTase and protein farnesylation in PBMN and tumors. In this aim he will also determine whether Ras mutation status in multiple myeloma tumors is predictive of response. The work will be carried out with R115777, an FTI available from the Cancer Therapy and Evaluation Program of the National Cancer Institute. The work proposed in this project will establish whether combination therapy of FTI with cytotoxic anticancer drugs is more beneficial than monotherapy and this will set the stage for future combination therapy in clinical trials.
| Zhu, Kuichun; Gerbino, Elvira; Beaupre, Darrin M et al. (2005) Farnesyltransferase inhibitor R115777 (Zarnestra, Tipifarnib) synergizes with paclitaxel to induce apoptosis and mitotic arrest and to inhibit tumor growth of multiple myeloma cells. Blood 105:4759-66 |
| Alsina, Melissa; Fonseca, Rafael; Wilson, Edward F et al. (2004) Farnesyltransferase inhibitor tipifarnib is well tolerated, induces stabilization of disease, and inhibits farnesylation and oncogenic/tumor survival pathways in patients with advanced multiple myeloma. Blood 103:3271-7 |
