Farnesyltransferase and geranylgeranyltransferase I inhibitors and cancer therapy: Lessons from mechanism and bench-to-bedside translational studies

In 1990, more than 10 years after the discovery that the low molecular weig ht GTPase Pas is a major contributor to human cancer, farnesylation, a lipi d posttranslational modification required for the cancer-causing activity o f Ras, emerged as a major target for the development of novel anticancer ag ents. However, it took only 5 years from 1993, when the first farnesyltrans ferase inhibitors (FTIs) were reported, to 1998 when results from the first phase I clinical trials were described. This rapid progress was due to the demonstration of outstanding antitumor activity and lack of toxicity of FT ls in preclinical models. Although, many FTIs are currently in phase II and at least one is in phase III clinical trial, the mechanism of FTI antitumo r activity is not known, In this review a brief summary of the development of FTIs as antitumor agents mill be given. The focus of the review will be on important mechanistic and bench-to-bedside translational issues. Among t he issues that will be addressed are: evidence for and against inhibition o f the prenylation of Pas and RhoB proteins in the mechanism of action of FT Is; implications of the alternative prenylation of K-Ras by geranylgeranyl- transferase I (when FTase is inhibited) in cancer therapy; GGTase I inhibit ors (GGTIs) as antitumor agents; effects of FTIs and GGTIs on cell cycle ma chinery and progression and potential mechanisms by which FTIs and GGTIs in duce apoptosis in human cancer cells. A thorough discussion about bench-to- bedside issues relating to hypothesis-driven clinical trials with proof-of- principle in man will also be included. This section will cover issues rela ting to whether the biochemical target (FTase) is inhibited and the level o f inhibition of FTase required for clinical response; are signaling pathway s such as H-Ras/PI3K/ Akt and/or K-Ras/Raf/MEK/Erk relevant biological read outs?; is Ras (particularly N-Ras and H-Ras) mutation status a good predict or of clinical response?; in phase I trials should effective biological dos e, not maximally tolerated dose, be used to determine phase II dose?; and f inally, in phase II/III trials what are the most appropriate clinical end p oints for anti-signaling molecules such as FTIs? Parts of this topic have b een recently reviewed (Sebti and Hamilton, 2000c).