Reduction of Circulating Cancer Cells and Metastases in Breast-Cancer Models by a Potent EphA2-Agonistic Peptide–Drug Conjugate

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.