EphA2 overexpression has been associated with metastasis in multiple cancer types, including melanomas and ovarian, prostate, lung, and breast cancers. We have recently proposed the development of peptide-drug conjugates (PDCs) using agonistic EphA2-targeting agents, such as the YSA peptide or its optimized version, 123B9. Although our studies indicated that YSA- and 123B9-drug conjugates can selectively deliver cytotoxic drugs to cancer cells in vivo, the relatively low cellular agonistic activities (i.e., the high micromolar concentrations required) of the agents toward the EphA2 receptor remained a limiting factor to the further development of these PDCs in the clinic. Here, we report that a dimeric version of 123B9 can induce receptor activation at nanomolar concentrations. Furthermore, we demonstrated that the conjugation of dimeric 123B9 with paclitaxel is very effective at targeting circulating tumor cells and inhibiting lung metastasis in breast-cancer models. These studies represent an important step toward the development of effective EphA2-targeting PDCs.

中文翻译：

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有效的EphA2-激动肽-药物缀合物在乳腺癌模型中减少循环癌细胞和转移。

EphA2过表达与多种癌症类型的转移相关，包括黑色素瘤和卵巢癌，前列腺癌，肺癌和乳腺癌。我们最近提出了使用激动性EphA2靶向剂（例如YSA肽或其优化版本123B9）开发肽-药物缀合物（PDC）的方法。尽管我们的研究表明YSA-和123B9-药物偶联物可以在体内选择性地向癌细胞递送细胞毒性药物，但是该药物对EphA2受体的相对较低的细胞激动活性（即所需的高微摩尔浓度）仍然是这些PDC在临床上的进一步发展。在这里，我们报道123B9的二聚体版本可以诱导纳摩尔浓度的受体激活。此外，我们证明了紫杉醇与二聚体123B9的结合在靶向循环肿瘤细胞和抑制乳腺癌模型中的肺转移方面非常有效。这些研究代表了开发有效的靶向EphA2的PDC的重要一步。