Pharmacotherapy of Hematologic Malignancies with Tipifarnib

Abstract

The illumination of cellular processes in cancer has revolutionized oncology drug development leading to a shift from non-specific chemotherapy to the selective targeting of tumorigenic signal transduction pathways. Farnesyltransferase inhibitors (FTIs) target proteins needing prenylation for functioning, thus inhibiting a wide variety of molecular targets crucial for cell proliferation and survival. Tipifarnib (R115777, Zarnestra®), a potent and specific inhibitor of Farnesyltransferase, can attain strong inhibition of tumor growth in preclinical models. As a single agent, tipifarnib has demonstrated activity in several hematologic malignancies, namely acute myeloid leukemia, myelodysplastic syndrome, chronic myeloid leukemia and multiple myeloma. However, considering the complexity of the molecular aberrations implicated in the pathogenesis of hematologic neoplasms, it is rather unlikely that monotherapy with tipifarnib will serve as a stand-alone treatment approach. Indeed, improved results have been achieved by combining tipifarnib with other anticancer agents, whereas the first efforts for the identification of molecular predictors of response are reporting intriguing results. Ongoing trials are anticipated to define the exact role of tipifarnib in the treatment of hematologic malignancies.