Farnesyl transferase inhibitors in clinical development

Abstract

Farnesyl transferase (FT) inhibitors block the main post-translational modification of the Ras protein, thus interfering with its localisation to the inner surface of the plasma membrane and subsequent activation of downstream effectors. Although initially developed as a strategy to target Ras in cancer, FT inhibitors have subsequently been acknowledged as acting by additional and more complex mechanisms that may extend beyond Ras, involving RhoB, centromere-binding proteins and probably other farnesylated proteins. SCH66336 (lonafarnib, Sarasar™, Schering-Plough), a tricyclic orally active FT inhibitor, was the first of these compounds to undergo clinical development. Gastrointestinal tract toxicities and fatigue have qualified as dose-limiting toxicities in all Phase I/II studies. Evidence of clinical activity has been reported. Lonafarnib combination studies with both gemcitabine and paclitaxel have been carried out. No unexpected toxicities were observed in these Phase I studies, while encouraging clinical activity was observed mainly in pancreatic cancer and non-small cell lung cancer. Further combination studies are ongoing. R115777 (Zarnestra™, Janssen Pharmaceutica) is another orally active FT competitive inhibitor in clinical development. Single-agent Phase I/II studies have shown that myelotoxicity and neurotoxicity are dose-limiting toxicities; intermittent schedule is probably better tolerated; antitumour activity is observed particularly in breast cancer and haematological malignancies. A number of combination studies with R115777 have been carried out. A recently completed, large Phase III trial comparing gemcitabine plus R115777 versus gemcitabine plus placebo in advanced pancreatic cancer has failed to demonstrate any survival benefit in the R115777 arm. BMS-214662 is the third FT inhibitor in clinical development. It has the main advantage of being cytotoxic in nature, rather than cytostatic, and potent in vivo antitumour activity has been reported. A major drawback for BMS-214662 is its severe gastrointestinal and liver toxicities, which prevent the achievement of adequate systemic exposures following the oral route. Alternative ways of interference with the ras oncogene pathway, in particular inhibition of ras downstream effectors, are discussed and early clinical data are presented.