Chimeric CCL2 and CCL8 Diphtheria Toxin Peptides Effectively Inhibit Human Breast Tumor Growth and Prolong Survival in Mice.

Breast cancer remains a significant global health challenge, with current therapies often limited by resistance and systemic toxicity. Chemokine receptors, like CCR2 which binds CCL2 and CCL8, are crucial for tumor onset and progression, influencing the tumor microenvironment (TME) and immune cell infiltration. However, the high redundancy among chemokine ligands and their receptors complicates therapeutic targeting. This redundancy necessitates novel strategies to leverage these pathways for effective cancer management, particularly for aggressive forms like hormone-negative breast cancer.

Researchers developed novel cytotoxic peptides, DTCCL2 and DTCCL8, by conjugating CCL2 and CCL8 chemokines to diphtheria toxin. These recombinant proteins were evaluated for anticancer activity in vitro in cultured breast cancer cells and in vivo in mice. The in vivo models included mice bearing human breast cancer cell lines and hormone-negative breast cancer patient-derived xenografts (PDXs). The study assessed the uptake profiles of these cytotoxic analogs in tumor explants ex vivo before and after therapy to understand their cellular penetration and distribution.

Both DTCCL2 and DTCCL8 analogs demonstrated significant cytotoxicity against breast cancer cells in vitro. In in vivo mouse models, these peptides produced substantial anticancer activity, inhibiting tumor growth and prolonging survival in the PDX model. Initial in vitro uptake showed approximately 80% of breast cancer cells positive for both peptides, while 15%-20% were negative for either or both.

Ex vivo analysis of tumor explants revealed that simultaneous positivity for DTCCL2 and DTCCL8 increased to >95% after therapy, with less than 5% of cells showing neither peptide uptake. These results underscore the potential of these chimeric peptides to effectively target and treat human breast tumors.