Farnesyltransferase inhibitor therapy in acute myelogenous leukemia.
Acute myelogenous leukemia (AML) remains a clinical challenge with poor long-term survival. Low remission rates and high treatment-related mortality persist as major obstacles, particularly in older patients. The design of novel agents based on the identification of genetic lesions and aberrant signaling pathways provides opportunity to improve the standard treatment paradigm of intensive cytotoxic chemotherapy. Farnesyltransferase inhibitors (FTIs) show potential to fill this niche. The preclinical concept of farnesyltransferase blockade as a targeted therapy against oncogenic Ras has clearly evolved with the recognition that many proteins involved signaling pathways in tumor cells undergo farnesylation. Phase I/II trials of FTI monotherapy in AML demonstrate encouraging responses and good tolerability. The FTI tipifarnib (R115777, Zarnestra; Johnson & Johnson, Titusville, NJ) has advanced the furthest in clinical trials, with the most promising activity in previously untreated, high-risk AML patients. A major emphasis of current clinical studies has been to analyze potential candidate genes and signaling pathways modified by FTIs in order to identify mechanisms of response and resistance. Preclinical concepts related to the development of FTIs, the rationale for their use in AML, and efficacy and safety results from recent clinical trials are evaluated in this paper.
Gotlib
Jason
J
Division of Hematology, Stanford Cancer Center, 875 Blake Wilbur Drive, Stanford, CA 94305, USA. jason.gotlib@stanford.edu
D000208:Acute Disease; D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D015331:Cohort Studies; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors*; D006410:Hematopoiesis / Q000187:drug effects; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000201:enzymology; D015337:Multicenter Studies as Topic; D009363:Neoplasm Proteins / Q000187:drug effects / Q000378:metabolism; D017368:Protein Prenylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D016896:Treatment Outcome; D018631:ras Proteins / Q000502:physiology
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D018125:Receptors, Transforming Growth Factor beta; D051231:Farnesyltranstransferase; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018631:ras Proteins