Farnesyltransferase and geranylgeranyltransferase I inhibitors in cancer therapy: important mechanistic and bench to bedside issues

The fact that proteins such as Pas, Pac and RhoA require farnesylation or g eranylgeranylation to induce malignant transformation prompted many investi gators to develop farnesyltransferase (FTase) and geranylgeranyltransferase I (GGTase I) inhibitors (FTIs and GGTIs, respectively) as novel anticancer drugs. Although FTIs have been shown to antagonise oncogenic signalling, r everse malignant transformation, inhibit human tumour growth in nude mice a nd induce tumour regression in transgenic mice without any signs of toxicit y, their mechanism of action is not known. This review will focus on import ant mechanistic issues as well as bench to bedside translational issues. Th ese will include the relevance to cancer therapy of the alternative geranyl geranylation of K-Ras when FTase is inhibited; a thorough discussion about evidence for and against the involvement of inhibition of prenylation of Pa s and RhoB in the mechanism of FTIs' antitumour activity as well as effects of FTIs and GGTIs on the cell cycle machinery and the dynamics of bipolar spindle formation and chromosome alignment during mitosis. Bench to bedside issues relating to the design of hypothesis-driven clinical trials with bi ochemical correlates for proof-of-concept in man will also be discussed. Th is will include Phase I issues such as determining maximally tolerated dose (MTD) versus effective biological dose (EBD), as well as whether Phase II trials are still needed for clinical evaluations of anti-signalling agents. Other questions that will be addressed include: what levels of inhibition of FTase activity are required for tumour response in Phase II clinical eva luations? What FTase substrates are most relevant as biochemical correlates ? Are signalling pathways such as H-Ras/PI3W/Akt and K-Ras/Raf/MEK/Erk sign ificant biological readouts? Does Ras mutation status predict response? Wha t are appropriate clinical end-points for FTI Phase II trials? For this lat ter important question, time to tumour progression, median survival, percen tage of patients that progress, clinical benefits and improvement in qualit y of life will all be discussed.