Second-generation inhibitors of fatty acid synthase for lung cancer treatment

Abstract

18185 Fatty acid synthase (FAS) is highly expressed in many human cancers, including lung cancers. Previous work has shown that blocking FAS activity by cerulenin, a natural antibiotic, or C75, a first-generation synthetic small molecule, leads to apoptosis in cells that overexpress this enzyme. However, the use of C75 is limited by the dose-dependent anorexia that appears to be associated with stimulation of fatty acid oxidation. Pharmacokinetics studies show that the activity of C75 peaks within hours of administration and by 24 hours, approximately 80% of activity is lost. Thus, the effectiveness of C75 is limited by this short duration of anti-neoplastic activity and the prolonged anorexic effects.Several second-generation novel FAS-inhibitory compounds have been synthesized that show significant inhibition of FAS, without parallel stimulation of fatty acid oxidation. Among the most promising of the compounds is C93, which inhibits FAS at nearly equal potency as C75, but has significantly less stimulation of fatty acid oxidation. We treated mice with xenografts (orthotopic and subcutaneous) developed from 3 different human lung cancer cell lines (H460, A549, and LX-7) with daily intraperitoneal injections of C93 (5 days/week) at 50 mg/kg for 4 weeks and observed significant (up to 70%) inhibition of tumor growth in all xenograft models tested. Furthermore, no significant weight loss and no organ-specific toxicity were recognized in treated animals. These results suggest that it is possible to pharmacologically uncouple inhibition of FAS from stimulation of fatty acid oxidation, and thus achieve anti-neoplastic activity by inhibition of FAS without significant drug-induced anorexia. Finally, we tested an oral formulation of C93 with the intent of developing a dosing protocol suitable for clinical applications. Similar levels of drug in tumor tissue, and similar inhibition of fatty acid synthase enzyme activity, were seen after oral and intraperitoneal administrations of drug. Furthermore, repeated oral administration of C93 to animals with subcutaneous H460 lung cancer xenografts inhibited tumor growth to a similar level observed after intraperitoneal administration. Thus, fatty acid synthase appears to be a promising target for lung cancer treatment. No significant financial relationships to disclose.