Enhancing ²²³Ra Treatment Efficacy by Anti-<b>β</b>1 Integrin Targeting.

Abstract

²²³Ra is an α-emitter approved for the treatment of bone metastatic prostate cancer (PCa), which exerts direct cytotoxicity toward PCa cells near the bone interface, whereas cells positioned in the core respond poorly because of short α-particle penetrance. β1 integrin (β1I) interference has been shown to increase radiosensitivity and significantly enhance external-beam radiation efficiency. We hypothesized that targeting β1I would improve ²²³Ra outcome. <b>Methods:</b> We tested the effect of combining ²²³Ra and anti-β1I antibody treatment in PC3 and C4-2B PCa cell models expressing high and low β1I levels, respectively. In vivo tumor growth was evaluated through bioluminescence. Cellular and molecular determinants of response were analyzed by ex vivo 3-dimensional imaging of bone lesions and by proteomic analysis and were further confirmed by computational modeling and in vitro functional analysis in tissue-engineered bone mimetic systems. <b>Results:</b> Interference with β1I combined with ²²³Ra reduced PC3 cell growth in bone and significantly improved overall mouse survival, whereas no change was achieved in C4-2B tumors. Anti-β1I treatment decreased the PC3 tumor cell mitosis index and spatially expanded ²²³Ra lethal effects 2-fold, in vivo and in silico. Regression was paralleled by decreased expression of radioresistance mediators. <b>Conclusion:</b> Targeting β1I significantly improves ²²³Ra outcome and points toward combinatorial application in PCa tumors with high β1I expression.