Potent Anticancer Activity of CXCR4-Targeted Nanostructured Toxins in Aggressive Endometrial Cancer Models

Simple Summary The fact that most endometrial cancer (EC) patients overexpress the CXCR4 receptor in tumor tissue, especially at incurable advanced stages, opens an avenue for developing novel therapies targeting CXCR4(+) EC cells to add new armamentarium against this malignancy. We have generated novel CXCR4-targeted nanotoxins, T22-DITOX-H6 and T22-PE24-H6, which we here evaluate in EC mouse models. We observed a selective killing of CXCR4(+) EC cells by apoptosis induction in cultured cells as well as in tumor models, which inhibit tumor growth and increase mouse survival after repeated intravenous doses. Moreover, T22-DITOX-H6 induced a significant block of metastasis dissemination without toxicity in non-tumor tissues. Therefore, both nanotoxins may become alternative therapeutics for CXCR4(+) high-risk EC patients, who nowadays lack effective therapies. Patients with advanced endometrial cancer (EC) show poor outcomes. Thus, the development of new therapeutic approaches to prevent metastasis development in high-risk patients is an unmet need. CXCR4 is overexpressed in EC tumor tissue, epitomizing an unexploited therapeutic target for this malignancy. The in vitro antitumor activity of two CXCR4-targeted nanoparticles, including either the C. diphtheriae (T22-DITOX-H6) or P. aeruginosa (T22-PE24-H6) toxin, was evaluated using viability assays. Apoptotic activation was assessed by DAPI and caspase-3 and PARP cleavage in cell blocks. Both nanotoxins were repeatedly administrated to a subcutaneous EC mouse model, whereas T22-DITOX-H6 was also used in a highly metastatic EC orthotopic model. Tumor burden was assessed through bioluminescence, while metastatic foci and toxicity were studied using histological or immunohistochemical analysis. We found that both nanotoxins exerted a potent antitumor effect both in vitro and in vivo via apoptosis and extended the survival of nanotoxin-treated mice without inducing any off-target toxicity. Repeated T22-DITOX-H6 administration in the metastatic model induced a dramatic reduction in tumor burden while significantly blocking peritoneal, lung and liver metastasis without systemic toxicity. Both nanotoxins, but especially T22-DITOX-H6, represent a promising therapeutic alternative for EC patients that have a dismal prognosis and lack effective therapies.