Extending the scope of FTIs

Advances in molecular biology and the understanding of signal transduction are allowing us to identify novel targets for the development of drugs for hematologic malignancies. One such potential target is farnesyl transferase, the enzyme responsible for the prenylation of proteins. Prenylation, the addition of a 15-carbon unsaturated polymer derived from the lipid pathway (a farnesyl group) appears to be important in posttranslational modification of several proteins critical to cell signaling, proliferation, and differentiation. Farnesyl transferase inhibitors (FTIs) have been developed to obstruct this process.

FTIs have demonstrated anticancer activity as single agents and in combination with standard cytotoxic chemotherapy in solid tumors. In the first clinical trial of an FTI in the hematologic malignancies, Karp et al (Blood. 2001;97:3361-3369) demonstrated both efficacy and tolerability of FTI R115777 (Zarnestra) in patients with acute leukemias. In this issue Cortes and colleagues (page 1692) report their encouraging results of a clinical trial of this agent in patients with a variety of hematologic malignancies: CML, myelofibrosis, and multiple myeloma.

Patients were treated at a dose of 600 mg orally twice a day for 4 weeks every 6 weeks. Responses were seen in 7 of 22 patients with CML, 4 of 8 patients with myelofibrosis, and only 1 of 10 patients with myeloma. This dosing schedule required dose interruptions and/or reductions in 58% of the patients. Alternate schedules or doses might further enhance the efficacy, by allowing prolonged administration if toxicity is decreased.

The authors also report their correlation of response with baseline VEGF levels, as well as with changes in VEGF concentrations with therapy, a finding that they wish to pursue in further studies. Despite uncertainty about the true target of FTIs, this agent has promising activity in a variety of hematologic malignancies, and further studies are warranted.