Targeting of endothelial expressed prostate specific membrane antigen for endogenous radiotherapy of triple negative breast cancer

Ziel/Aim:

The triple negative phenotype of breast cancer is associated with extremely high risk of relapse due to the lack of targeted therapies, intra- and inter-tumoral heterogeneity, and to the inherent and acquired resistance to therapies. In this study, we evaluate the potential of prostate specific membrane antigen (PSMA) as vascular target for endogenous radiotherapy of triple negative breast cancer (TNBC).

Methodik/Methods:

The pro-angiogenic potential of breast cancer cell lines with different phenotypes was evaluated in a co-cultivation chamber system. Tube formation of endothelial HUVEC cells was monitored after staining by microscopy. For mimicking of the therapeutic application, tube formation potential and vitality of tumor-conditioned HUVEC cells were assessed following an incubation with Lu-177-PSMA-L in the chamber system. A binding study with Ga-68-labelled tracer was used to indicate targeting potential of PSMA on tumor-conditioned HUVEC cells. For in vivo experiments, NUDE mice were xenografted with TNBC cells MDA-MB231. PSMA-specific staining and micro autoradiography with Ga-68-labelled tracer were conducted to visualize targeting of PSMA on tumor-associated endothelium ex vivo.

Ergebnisse/Results:

We detected a high pro-angiogenetic potential of triple negative breast cancer cells MDA-MB231 on tube formation by endothelial HUVEC cells. The induced endothelial expression of PSMA was efficiently addressed by radiolabeled PSMA-specific ligand. Lu-177-PSMA-617 strongly impaired the vitality and angiogenic potential of HUVEC cells. In vivo, as visualized by small animal µPET/CT camera system, radiolabeled PSMA-specific ligand accumulated specifically in the triple negative breast cancer xenograft. An ex vivo immunofluorescence analysis confirmed the localization of PSMA on MDA-MB231 xenograft associated endothelial cells.

Schlussfolgerungen/Conclusions:

Here we demonstrate PSMA as promising target for anti-angiogenic endogenous radiotherapy of triple negative breast cancer.