Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, Georgia, USA.
Cancer. 2011 Sep 1;117(17):4049-59. doi: 10.1002/cncr.26004. Epub 2011 Mar 1.
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 pretreatment 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 1 of 4 dosing cohorts: 1) 30 mg/m², 100 mg; 2) 36 mg/m², 100 mg; 3) 30 mg/m², 150 mg; or 4) 36 mg/m², 150 mg of DTX intravenously weekly, LNF orally twice daily, 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 antidiarrheal 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 < .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.
Lonafarnib（LNF）是一种法尼基转移酶（FTase）抑制剂，在临床前模型和早期临床试验中已显示与紫杉烷类药物具有协同作用。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，有助于确定更有可能从该方案中获益的患者群体。这项初步研究通过比较预处理和后处理肿瘤活检，评估了 LNF 和多西紫杉醇（DTX）联合治疗在难治性实体瘤中的生物学效应。
患有组织学证实的局部晚期或转移性实体恶性肿瘤且对标准治疗耐药或无有效治疗方法的患者符合条件。患者随机分配到 4 个剂量组之一：1）30mg/m²，100mg；2）36mg/m²，100mg；3）30mg/m²，150mg；或 4）36mg/m²，150mg 的 DTX 静脉内每周一次，LNF 口服每天两次。
在纳入的 38 名患者中，36 名患者接受了治疗，29 名患者可进行毒性和反应评估。除 28%的患者发生 3/4 级腹泻外，LNF 和 DTX 的联合用药在所有队列中均耐受，这可以通过积极的止泻方案来控制。7 名患者从该联合治疗中获得了有临床意义的获益；这些患者的基础 FTase-βmRNA 表达水平明显低于研究人群的平均水平（P<.05）。评估了临床获益与微管蛋白乙酰化含量以及基础乙酰化微管蛋白含量的相关性。然而，没有发现显著相关性。
尽管患者人数较少，但这些发现支持我们的临床前机制研究，并需要进一步的临床研究，将 FTase-βmRNA 表达作为一种潜在的预测生物标志物，以选择更丰富的患者群体来研究紫杉烷和 FTase 抑制剂联合治疗的效果。
