University of Texas M.D. Anderson Cancer Center, Investigational Cancer Therapeutics, 1515 Holcombe Blvd., Unit 455, Houston 77030, USA.
Expert Opin Investig Drugs. 2010 Dec;19(12):1569-80. doi: 10.1517/13543784.2010.535516. Epub 2010 Nov 18.
Farnesyltransferase inhibitors (FTIs) target multiple pathways implicated in the pathogenesis of solid and hematologic malignancies.
Novel preclinical and clinical data on FTIs.
Results of clinical trials of FTIs are critically summarized: Phase I - II studies demonstrated that tipifarnib (the most extensively investigated FTI) had antileukemic activity. The rates of complete response (CR), partial response (PR) and/or CR with incomplete platelet recovery (CRp) in patients with MDS and refractory/poor-risk AML were 5 - 25% and 11 - 14%, respectively (hematological improvement, 17 - 35% and 8 - 9.5%, respectively). A Phase III study comparing tipifarnib with best supportive care, including hydroxyurea in patients with untreated AML ≥ 70 years old showed no survival benefit in the tipifarnib arm. A two-gene classifier (RASGRP1:APTX gene expression ratio) predicted response and survival, indicating that a two-gene expression assay may help select patients with AML who would benefit from tipifarnib.
Patient selection should become a priority for targeted agent drug development. Clinical trials selecting patients who would benefit from FTIs should be designed to define the role of FTIs in the treatment of hematological malignancies and solid tumors.
法尼基转移酶抑制剂（FTIs）针对多个途径涉及实体瘤和血液恶性肿瘤的发病机制。
新颖的临床前和临床数据的 FTIs。
FTIs 的临床试验结果进行了批判性总结：阶段 I - II 研究表明，替比法尼（最广泛研究的 FTI）具有抗白血病活性。完全缓解（CR），部分缓解（PR）和/或不完整血小板恢复的 CR（CRp）在 MDS 和难治性/低危 AML 患者中的率分别为 5 - 25%和 11 - 14%（血液学改善，分别为 17 - 35%和 8 - 9.5%）。一项比较替比法尼与最佳支持治疗的 III 期研究，包括羟基脲在未经治疗的 AML ≥ 70 岁的患者中，替比法尼组没有生存获益。一个双基因分类器（RASGRP1：APTX 基因表达比）预测反应和生存，表明双基因表达测定可能有助于选择将从替比法尼获益的 AML 患者。
患者选择应该成为靶向药物开发的优先事项。临床试验选择将从 FTIs 获益的患者，应该设计的作用，以确定 FTIs 在治疗血液恶性肿瘤和实体瘤。
