Advanced Therapeutics, BC Cancer Agency, Vancouver, British Columbia, Canada.
Breast Cancer Res. 2009;11(3):R25. doi: 10.1186/bcr2252. Epub 2009 May 1.
Substantial preclinical evidence has indicated that inhibition of integrin linked-kinase (ILK) correlates with cytotoxic/cytostatic cellular effects, delayed tumor growth in animal models of cancer, and inhibition of angiogenesis. Widely anticipated to represent a very promising therapeutic target in several cancer indications, it is increasingly evident that optimal therapeutic benefits obtained using ILK targeting strategies will only be achieved in combination settings. The purpose of this study was to investigate the therapeutic potential of the ILK small molecule inhibitor, QLT0267 (267), alone or in combination with chemotherapies commonly used to treat breast cancer patients.
A single end-point metabolic assay was used as an initial screen for 267 interactions with selected chemotherapeutic agents. These in vitro assays were completed with seven breast cancer cell lines including several which over-expressed human epidermal growth factor receptor 2 (Her2). One agent, docetaxel (Dt), consistently produced synergistic interactions when combined with 267. Dt/267 interactions were further characterized by measuring therapeutic endpoints linked to phosphorylated protein kinase B (P-AKT) suppression, inhibition of vascular endothelial growth factor (VEGF) secretion and changes in cytoarchitecture. In vivo efficacy studies were completed in mice bearing orthotopic xenografts where tumor growth was assessed by bioluminescence and calliper methods.
The combination of 267 and Dt resulted in increased cytotoxic activity, as determined using an assay of metabolic activity. Combinations of cisplatin, doxorubicin, vinorelbine, paclitaxel, and trastuzumab produced antagonistic interactions. Further endpoint analysis in cell lines with low Her2 levels revealed that the 267/Dt combinations resulted in: a three-fold decrease in concentration (dose) of 267 required to achieve 50% inhibition of P-AKT; and a dramatic disruption of normal filamentous-actin cellular architecture. In contrast to Her2-positive cell lines, three-fold higher concentrations of 267 were required to achieve 50% inhibition of P-AKT when the drug was used in combination with Dt. In vivo studies focusing on low Her2-expressing breast cancer cells (LCC6) implanted orthotopically demonstrated that treatment with 267/Dt engendered improved therapeutic effects when compared with mice treated with either agent alone.
The findings indicate that the 267/Dt drug combination confers increased (synergistic) therapeutic efficacy towards human breast cancer cells that express low levels of Her2.
大量的临床前证据表明，整合素连接激酶（ILK）的抑制作用与细胞毒性/细胞静止的细胞效应、动物癌症模型中的肿瘤生长延迟和血管生成抑制有关。预计在多种癌症适应证中代表一种非常有前途的治疗靶点，越来越明显的是，只有在联合治疗环境中才能获得使用 ILK 靶向策略获得的最佳治疗益处。本研究的目的是研究 ILK 小分子抑制剂 QLT0267（267）单独或与常用于治疗乳腺癌患者的化疗药物联合使用的治疗潜力。
使用单一终点代谢测定法作为与选定化疗药物相互作用的 267 初步筛选。这些体外测定法是用七种乳腺癌细胞系完成的，其中包括几种过表达人表皮生长因子受体 2（Her2）的细胞系。一种药物，多西紫杉醇（Dt），与 267 联合使用时始终产生协同作用。通过测量与磷酸化蛋白激酶 B（P-AKT）抑制、血管内皮生长因子（VEGF）分泌变化和细胞结构变化相关的治疗终点，进一步对 Dt/267 相互作用进行了表征。在携带原位异种移植物的小鼠中完成了体内疗效研究，通过生物发光和卡尺方法评估肿瘤生长。
使用代谢活性测定法确定，267 和 Dt 的组合导致细胞毒性活性增加。顺铂、阿霉素、长春瑞滨、紫杉醇和曲妥珠单抗的组合产生拮抗相互作用。在 Her2 水平较低的细胞系中进一步进行终点分析显示，267/Dt 组合导致：抑制 P-AKT 所需的 267 浓度（剂量）降低三分之一；以及正常丝状肌动蛋白细胞结构的急剧破坏。与 Her2 阳性细胞系相比，当药物与 Dt 联合使用时，需要高出三倍的 267 浓度才能达到 50%抑制 P-AKT。在专注于低 Her2 表达乳腺癌细胞（LCC6）原位植入的体内研究中，与单独用任一药物治疗的小鼠相比，用 267/Dt 治疗导致改善了治疗效果。
研究结果表明，267/Dt 药物组合赋予表达低水平 Her2 的人乳腺癌细胞更高的（协同）治疗效果。
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