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首页> 外文期刊>Molecular cancer therapeutics >CXCR4 Protein Epitope Mimetic Antagonist POL5551 Disrupts Metastasis and Enhances Chemotherapy Effect in Triple-Negative Breast Cancer
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CXCR4 Protein Epitope Mimetic Antagonist POL5551 Disrupts Metastasis and Enhances Chemotherapy Effect in Triple-Negative Breast Cancer

机译：CXCR4蛋白表位模拟拮抗剂POL5551破坏转移，增强了三阴性乳腺癌中的化疗效果

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The SDF-1 receptor CXCR4 has been associated with early metastasis and poorer prognosis in breast cancers, especially the most aggressive triple-negative subtype. In line with previous reports, we found that tumoral CXCR4 expression in patients with locally advanced breast cancer was associated with increased metastases and rapid tumor progression. Moreover, high CXCR4 expression identified a group of bone marrow-disseminated tumor cells (DTC)-negative patients at high risk for metastasis and death. The protein epitope mimetic (PEM) POL5551, a novel CXCR4 antagonist, inhibited binding of SDF-1 to CXCR4, had no direct effects on tumor cell viability, but reduced migration of breast cancer cells in vitro. In two orthotopic models of triple-negative breast cancer, POL5551 had little inhibitory effect on primary tumor growth, but significantly reduced distant metastasis. When combined with eribulin, a chemotherapeutic microtubule inhibitor, POL5551 additively reduced metastasis and prolonged survival inmice after resection of the primary tumor compared with single-agent eribulin. Hypothesizing that POL5551 may mobilize tumor cells from their microenvironment and sensitize them to chemotherapy, we used a "chemotherapy framing" dosing strategy. When administered shortly before and after eribulin treatment, three doses of POL5551 with eribulin reduced bone and liver tumor burden more effectively than chemotherapy alone. These data suggest that sequenced administration of CXCR4 antagonists with cytotoxic chemotherapy synergize to reduce distant metastases. (C) 2015 AACR.
机译：SDF-1受体CXCR4与早期转移和乳腺癌预后较差，特别是最具侵略性的三阴性亚型相关。符合以前的报道，我们发现局部晚期乳腺癌患者的肿瘤CXCR4表达与转移增加和肿瘤快速进展相关。此外，高CXCR4表达鉴定了一组骨髓播放肿瘤细胞（DTC）的患者，其高风险转移和死亡。蛋白质表位模拟物（PEM）POL5551，一种新型CXCR4拮抗剂抑制SDF-1至CXCR4的结合，对肿瘤细胞活力没有直接影响，但在体外减少乳腺癌细胞的迁移。在三重阴性乳腺癌的两种原位模型中，POL5551对原发性肿瘤生长几乎没有抑制作用，但显着降低了远处转移。当与Eribulin结合时，化学治疗性微管抑制剂，POL5551与单孕二林蛋白相比，在切除原发性肿瘤后，POL5551在切除原发性肿瘤后，转移和延长的存活。假设POL5551可以从其微环境中调动肿瘤细胞并使它们敏化到化疗，我们使用了“化疗框架”给药策略。当伯蛋白治疗前后不久和之后施用时，三剂量的POL551，纤维蛋白比单独的化疗更有效地减少了骨骼和肝肿瘤负荷。这些数据表明，具有细胞毒性化疗的CXCR4拮抗剂的施用协同减少远处转移。 （c）2015年AACR。

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