Unit of Translational Research, Catalan Institute of Oncology-Girona, Avenida de Francia s/n, E-17007 Girona, Catalonia, Spain.
Drug Resist Updat. 2011 Aug-Oct;14(4-5):212-23. doi: 10.1016/j.drup.2011.04.003. Epub 2011 May 19.
Ideal oncology drugs would be curative after a short treatment course if they could eliminate epithelium-originated carcinomas at their non-invasive, pre-malignant stages. Such ideal molecules, which are expected to molecularly abrogate all the instrumental mechanisms acquired by migrating cancer stem cells (CSCs) to by-pass tumour suppressor barriers, might already exist. We here illustrate how system biology strategies for repositioning existing FDA-approved drugs may accelerate our therapeutic capacity to eliminate CSC traits in pre-invasive intraepithelial neoplasias. First, we describe a signalling network signature that overrides bioenergetics stress- and oncogene-induced senescence (OIS) phenomena in CSCs residing at pre-invasive lesions. Second, we functionally map the anti-malarial chloroquine and the anti-diabetic metformin ("old drugs") to their recently recognized CSC targets ("new uses") within the network. By discussing the preclinical efficacy of chloroquine and metformin to inhibiting the genesis and self-renewal of CSCs we finally underscore the expected translational impact of the "old drugs-new uses" repurposing strategy to open a new CSC-targeted chemoprevention era.
如果理想的肿瘤药物能够在短疗程内消除非侵袭性、恶性前阶段的上皮源性癌，那么它们将是治愈性的。这样的理想分子有望从分子上消除迁移性癌症干细胞 (CSC) 绕过肿瘤抑制屏障所获得的所有工具机制，它们可能已经存在。我们在这里说明如何重新定位现有的 FDA 批准药物的系统生物学策略，以加速我们消除侵袭前上皮内肿瘤中 CSC 特征的治疗能力。首先，我们描述了一种信号网络特征，该特征可以克服位于侵袭前病变的 CSC 中的生物能量应激和癌基因诱导的衰老 (OIS) 现象。其次，我们在网络内将抗疟药氯喹和抗糖尿病药二甲双胍（“旧药”）功能映射到它们最近被识别的 CSC 靶标（“新用途”）。通过讨论氯喹和二甲双胍抑制 CSC 的发生和自我更新的临床前疗效，我们最终强调了“旧药-新用途”重新定位策略的预期转化影响，以开启一个新的 CSC 靶向化学预防时代。
