RT Journal Article
SR Electronic
T1 Enhancing <sup>223</sup>Ra Treatment Efficacy by Anti-<strong>β</strong>1 Integrin Targeting
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 1039
OP 1045
DO 10.2967/jnumed.121.262743
VO 63
IS 7
A1 Claudia Paindelli
A1 Stefano Casarin
A1 Feng Wang
A1 Luis Diaz-Gomez
A1 Jianhua Zhang
A1 Antonios G. Mikos
A1 Christopher J. Logothetis
A1 Peter Friedl
A1 Eleonora Dondossola
YR 2022
UL http://jnm.snmjournals.org/content/63/7/1039.abstract
AB 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. Methods: 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. Results: 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. Conclusion: Targeting β1I significantly improves 223Ra outcome and points toward combinatorial application in PCa tumors with high β1I expression.