A phase II trial of AS1411 (a novel nucleolin-targeted DNA aptamer) in metastatic renal cell carcinoma.
A phase II trial of AS1411 (a novel nucleolin-targeted DNA aptamer) in metastatic renal cell carcinoma.
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DOI：
10.1007/s10637-013-0045-6
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发表时间：
2014-02
影响因子：
3.4
通讯作者：
Laber DA
中科院分区：
文献类型：
--
作者：
Rosenberg JE;Bambury RM;Van Allen EM;Drabkin HA;Lara PN Jr;Harzstark AL;Wagle N;Figlin RA;Smith GW;Garraway LA;Choueiri T;Erlandsson F;Laber DA
DNA适体代表了抗癌药物的一种新策略。这些化合物是DNA的短序列，其通过在类似于抗体-抗原结合的相互作用中对靶蛋白的形状特异性识别而具有蛋白质结合作用。AS 1411是一种靶向核仁素（一种在许多肿瘤类型中过表达的蛋白质）的DNA适体，在既往接受≥1种酪氨酸激酶抑制剂治疗失败的转移性肾细胞癌（RCC）患者中进行了评价。我们提出了第一个手稿报告使用这种新型抗癌剂在人类。在这项II期、单组研究中，在28天周期的第1-4天连续静脉输注给予40 mg/kg/天的AS 1411，持续2个周期。主要终点为总缓解率;无进展生存期（PFS）和安全性为次要终点。35例患者入组并接受治疗; 33例完成了两个治疗周期。中位既往治疗次数为2次（范围1-7次）。1例患者（2.9%）对治疗有反应。反应是显著的（选定的靶肿瘤病变的最长直径之和减少84%）和持久的（患者在完成治疗后2年保持无进展）。在其他患者中未观察到反应。中位PFS为4个月。只有34%的患者发生了AS 1411相关不良事件，所有事件均为轻度或中度。AS 1411在患有转移性RCC的NSCLC患者中似乎具有有限的活性。然而，可以观察到罕见的、显著的和持久的反应，并且毒性低。进一步的研究与核仁素靶向化合物可能会受益于努力发现预测生物标志物的反应。目前，正在进行有前景的临床前研究，使用与传统细胞毒性药物结合的AS 1411选择性地将这些治疗药物递送至肿瘤细胞。DNA适体代表了一种在分子水平上靶向癌细胞的新方法，并将继续开发，以期改善癌症医学的治疗和成像。
DNA aptamers represent a novel strategy in anti-cancer medicine. These compounds are short sequences of DNA that have protein binding effects via shape specific recognition of a target protein in an interaction which is analogous to antibody-antigen binding. AS1411, a DNA aptamer that targets nucleolin (a protein which is overexpressed in many tumor types), was evaluated in patients with metastatic, predominantly clear-cell, renal cell carcinoma (RCC) who had failed treatment with ≥1 previous tyrosine kinase inhibitor. We present the first manuscript reporting the use of this novel anti-cancer agent in humans. In this phase II, single-arm study, AS1411 was administered at 40 mg/kg/day by continuous intravenous infusion on days 1–4 of a 28-day cycle, for two cycles. Primary endpoint was overall response rate; progression-free survival (PFS) and safety were secondary endpoints. 35 patients were enrolled and treated; 33 completed two treatment cycles. Median number of prior therapies was 2 (range 1–7). One patient (2.9%) had a response to treatment. The response was dramatic (84% reduction in the sum of longest diameters of selected target tumor lesions) and durable (the patient remains free of progression 2 years after completing therapy). No responses were seen in the other patients. Median PFS was 4 months. Only 34% of patients had an AS1411-related adverse event, all of which were mild or moderate. AS1411 appears to have limited activity in unselected patients with metastatic RCC. However, rare, dramatic and durable responses can be observed and toxicity is low. Further studies with nucleolin targeted compounds may benefit from efforts to discover predictive biomarkers of response. Currently, promising pre-clinical studies are ongoing using AS1411 conjugated to traditional cytotoxic agents to selectively deliver these treatments to tumor cells. DNA aptamers represent a novel way to target cancer cells at a molecular level and continue to be developed with a view to improving treatment and imaging in cancer medicine.