Effective treatment of human breast tumors by chimeric CCL2 and CCL8 diphtheria toxin cytotoxic peptides.

Abstract

Objective: Chemokine receptors play crucial roles in tumor onset and progression, but the high redundancy between ligands and their receptors limits the possibilities to leverage them therapeutically for cancer management. To overcome this limitation, we developed chimeric chemokine peptides in which CCL2 and CCL8 were conjugated to diphtheria toxin (DT) and evaluated their antitumor activity.

Methods: Cytotoxic peptides DTCCL2 and DTCCL8 were produced as recombinant proteins, and their anticancer activity was tested in vitro in cultured cells and in vivo in tumor-bearing mice. The uptake of the cytotoxic analogs was evaluated before and after therapy in tumor explants ex vivo.

Results: Both analogs were cytotoxic to breast cancer cells in vitro and produced significant anticancer activity in vivo in mice bearing human breast cancer lines and hormone-negative breast cancer patient-derived xenografts (PDXs). In vitro, the peptide conjugates exhibited overlapping uptake profiles, with about 80% of the breast cancer cells being positive for both peptides and about 15%-20% of the cells being negative for either or both of the cytotoxic peptides. In tumor explants cultured ex vivo, simultaneous positivity for DTCCL2 and DTCCL8 increased to >95%, with less than 5% of the cells showing neither DTCCL8 nor DTCCL2 uptake. Treatment of breast cancer-bearing mice with DTCCL8 or DTCCL2 significantly inhibited tumor growth and prolonged survival in the PDX model.

Conclusion: These results support the feasibility of cytotoxic peptide conjugates for breast cancer management and show that receptor expression profiles in vitro do not accurately forecast tumoral positivity.