Selective Small Molecule Stat3 Inhibitor Reduces Breast Cancer Tumor-Initiating Cells and Improves Recurrence Free Survival in a Human-Xenograft Model
Selective Small Molecule Stat3 Inhibitor Reduces Breast Cancer Tumor-Initiating Cells and Improves Recurrence Free Survival in a Human-Xenograft Model
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DOI：
10.1371/journal.pone.0030207
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发表时间：
2012-08-06
期刊：
影响因子：
3.7
通讯作者：
Chang, Jenny C.
中科院分区：
文献类型：
--
作者：
Dave, Bhuvanesh;Landis, Melissa D.;Chang, Jenny C.
转移和疾病复发被认为是肿瘤起始细胞(TICs)的结果。此前，我们已经在乳腺癌中定义了CD44+/CD24-/低乳房形成致癌493-基因信号。在两个乳腺癌细胞株SUM159和BT549中进行的慢病毒shRNA筛查表明，STAT3是自我更新的关键节点。在确证工作中，用一种新的小分子靶向STAT3的SH2结构域减少了表达TIC标记(CD44+/CD24-/Low和ALDH+)的细胞的百分比和高表达人乳腺癌的SCID-beige小鼠p-STAT3异种移植瘤的乳房形成。重要的是，我们观察到在化疗耐药肿瘤模型中加入STAT3抑制剂后，与单独使用多西他赛相比，30天无复发生存率提高了四倍。因此，这些发现为选择性STAT3抑制剂的开发提供了强大的推动力，以提高p-STAT3过表达肿瘤患者的生存率。
Metastasis and disease relapse are hypothesized to result from tumor initiating cells (TICs). Previously, we have defined a CD44+/CD24-/low mammosphere-forming tumorigenic 493-gene signature in breast cancer. Stat3 was identified as a critical node in self-renewal based on an ongoing lentiviral shRNA screen being conducted in two breast cancer cell lines SUM159 and BT549. In corroborating work, targeting the SH2 domain of Stat3 with a novel small molecule decreased the percentage of cells expressing TIC markers (CD44+/CD24-/low and ALDH+) and mammosphere formation in p-Stat3 overexpressing human breast cancer xenografts in SCID-beige mice. Importantly, we observed a four-fold improvement in the 30-day recurrence-free survival relative to docetaxel alone with the addition of the Stat3 inhibitor in the chemoresistant tumor model. Thus, these findings provide a strong impetus for the development of selective Stat3 inhibitors in order to improve survival in patients with p-Stat3 overexpressing tumors.