Towards the first targeted therapy for triple-negative breast cancer: Repositioning of clofazimine as a chemotherapy-compatible selective Wnt pathway inhibitor
Towards the first targeted therapy for triple-negative breast cancer: Repositioning of clofazimine as a chemotherapy-compatible selective Wnt pathway inhibitor
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DOI：
10.1016/j.canlet.2019.02.018
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发表时间：
2019-01-01
期刊：
影响因子：
9.7
通讯作者：
Katanaev, Vladimir L.
中科院分区：
文献类型：
--
作者：
Ahmed, Kamal;Koval, Alexey;Katanaev, Vladimir L.
WNT信号在三阴性乳腺癌(TNBC)和其他几种癌症中过度激活，它的抑制成为一种有效的抗癌治疗方法。然而，市场上还没有针对Wnt途径的药物，也没有处于高级临床试验中。在这里，我们提供了全面的临床前证据，证明抗麻风药物氯法齐明对TNBC有效。氯法齐明在体外特异性地抑制一组TNBC细胞中典型的Wnt信号。在几种小鼠TNBC异种移植模型中，氯法齐明有效地抑制肿瘤生长，与体内抑制肿瘤中的Wnt途径有关。氯法齐明与阿霉素配伍良好，对肿瘤生长有相加抑制作用，无不良反应。它出色的药代动力学特征，中等剂量(但治疗有效)下没有严重的不良反应，它与细胞毒疗法的结合，以及新颖的作用机制，使氯法齐明成为重新定位临床试验的首选候选药物。我们的工作可能会带来抗WNT靶向治疗，这是目前缺乏靶向治疗的数千名患者迫切需要的。
Wnt signaling is overactivated in triple-negative breast cancer (TNBC) and several other cancers, and its suppression emerges as an effective anticancer treatment. However, no drugs targeting the Wnt pathway exist on the market nor in advanced clinical trials. Here we provide a comprehensive body of preclinical evidence that an anti-leprotic drug clofazimine is effective against TNBC. Clofazimine specifically inhibits canonical Wnt signaling in a panel of TNBC cells in vitro. In several mouse xenograft models of TNBC, clofazimine efficiently suppresses tumor growth, correlating with in vivo inhibition of the Wnt pathway in the tumors. Clofazimine is well compatible with doxorubicin, exerting additive effects on tumor growth suppression, producing no adverse effects. Its excellent and well-characterized pharmacokinetics profile, lack of serious adverse effects at moderate (yet therapeutically effective) doses, its combinability with cytotoxic therapeutics, and the novel mechanistic mode of action make clofazimine a prime candidate for the repositioning clinical trials. Our work may bring forward the anti-Wnt targeted therapy, desperately needed for thousands of patients currently lacking targeted treatments.