Farnesyl transferase expression determines clinical response to the docetaxel-lonafarnib combination in patients with advanced malignancies.
Farnesyl transferase expression determines clinical response to the docetaxel-lonafarnib combination in patients with advanced malignancies.
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DOI：
10.1002/cncr.26004
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发表时间：
2011-09-01
期刊：
影响因子：
6.2
通讯作者：
Khuri FR
中科院分区：
文献类型：
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作者：
Kauh J;Chanel-Vos C;Escuin D;Fanucchi MP;Harvey RD;Saba N;Shin DM;Gal A;Pan L;Kutner M;Ramalingam SS;Bender L;Marcus A;Giannakakou P;Khuri FR
洛那法尼（LNF）是一种蛋白法尼基转移酶（FTase）抑制剂，已在临床前模型和早期临床试验中显示出与紫杉烷类的协同活性。临床前研究结果表明，微管蛋白乙酰化和FTase表达水平可能是药物敏感性的重要决定因素，这将有助于确定更有可能从该方案中获益的患者人群。该初步研究通过比较治疗前和治疗后的肿瘤活检，评价了LNF和多西他赛（DTX）联合治疗在难治性实体瘤中的生物学效应。标准治疗难治性或无有效治疗的组织学证实的局部晚期或转移性实体恶性肿瘤患者合格。将患者随机分配至四个给药队列之一：（1）30 mg/m2、100 mg，（2）36 mg/m2、100 mg，（3）30 mg/m2、150 mg，或（4）36 mg/m2、150 mg DTX IV每周一次，LNF PO BID。在入组的38例患者中，36例接受了治疗，29例可进行毒性和缓解评估。除28%的3/4级腹泻发生率外，所有队列均耐受LNF和DTX的联合治疗，3/4级腹泻可通过积极的抗腹泻方案进行管理。7例患者从该联合治疗中获得了临床意义的获益;这些患者的基础FT酶-β mRNA表达水平显著低于平均研究人群水平（p<0.05）。评价了临床获益与微管蛋白乙酰化含量以及基础乙酰微管蛋白含量的相关性。尽管患者数量较少，但这些发现支持了我们的临床前机制研究，并保证了进一步的临床研究，使用FTase-beta mRNA表达作为潜在的预测生物标志物，以选择富集的患者人群来研究紫杉烷和FTase抑制剂联合治疗的效果。
Lonafarnib (LNF) is a protein farnesyl transferase (FTase) inhibitor that has shown synergistic activity with taxanes in preclinical models and early stage clinical trials. Preclinical findings suggested tubulin acetylation and FTase expression levels may be important determinants of drug sensitivity that would help identify patient populations more likely to benefit from this regimen. This pilot study evaluated the biological effects of LNF and docetaxel (DTX) combination therapy in refractory solid tumors by comparing pre- and post-treatment tumor biopsies. Patients with histologically-confirmed locally advanced or metastatic solid malignancies refractory to standard therapies or with no effective therapies available were eligible. Patients were randomized to one of four dosing cohorts: (1) 30mg/m2, 100mg, (2) 36mg/m2, 100mg, (3) 30mg/m2, 150mg, or (4) 36mg/m2, 150mg of DTX IV weekly, LNF PO BID, respectively. Of the 38 patients enrolled, 36 were treated, and 29 were evaluable for toxicity and response assessment. The combination of LNF and DTX was tolerated in all cohorts with the exception of a 28% incidence of grade 3/4 diarrhea which was manageable with aggressive anti-diarrheal regimens. Seven patients derived clinically meaningful benefit from this combination treatment; these patients had significantly lower basal FTase-beta mRNA expression levels than the mean study population level (p<0.05). Correlation of clinical benefit with tubulin acetylation content as well as basal acetyl-tubulin content were evaluated. However, no significant correlation was found. Despite the small number of patients, these findings support our preclinical mechanistic studies and warrant further clinical investigations using FTase-beta mRNA expression as a potential predictive biomarker to select for an enriched patient population to study the effects of taxane and FTase inhibitor combination therapies.