Protein farnesyltransferase inhibitors

Current systemic cytotoxic therapies for cancer are limited by their nonspecific mechanism of action, unwanted toxicities on normal tissues and short-term efficacy due to the emergence of drug resistance. However, identification of the molecular abnormalities in cancer, in particular the key proteins involved in abnormal cell growth, has resulted in various signal transduction inhibitor drugs being developed as new treatment strategies against the disease. Protein farnesyltransferase inhibitors (FTIs) were originally designed to target the Ras signal transduction pathway, although it is now clear that several other intracellular proteins are dependent on post-translational farnesylation (addition of a 15-carbon farnesyl moiety) for their function. Preclinical data revealed that although FTIs inhibit the growth of ras-transformed cells, they are also potent inhibitors of a wide range of cancer cell lines, many of which contain wild type ras. While understanding the mechanism of action of FTIs remains an important research goal, three different FTIs have entered clinical development. Several Phase I trials with each drug have explored different schedules for prolonged administration, and dose-limiting toxicities (DLTs) have varied from myelosuppression, gastrointestinal toxicity and neuropathy. Evidence for anticancer efficacy has come from a number of Phase II studies, not necessarily in tumour types containing ras mutations, which were the initial target for these drugs. Perhaps the most promising use for FTIs will be in combination with conventional cytotoxic drugs, based on preclinical data suggesting synergy, particularly with the taxanes. Clinical combination studies are in progress, and larger Phase II/III clinical trials are planned to see if FTIs can add to the efficacy of conventional therapies.